1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-acetamides and derivatives

ABSTRACT

Indole derivatives characterized by having a 1,3,4,9-tetrahydropyrano[3,4-b]indole or 1,3,4,9-tetrahydrothiopyrano[3,4-b]indole nucleus bearing a substituent in position 1, said substituent incorporating an acid, ester or amide function therein, are disclosed. The nucleus is further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7, 8, and 9. The derivatives are useful antiinflammatory, analgesic, antibacterial and antifungal agents and methods for their preparation and use are also disclosed.

This application is a continuation-in-part of our earlier-filed application Ser. No. 311,023 filed Nov. 30, 1972 now abandoned, which is a continuation-in-part of our earlier-filed application Ser. No. 289,714 filed Sept. 15, 1972 now pending, which is a continuation-in-part of our earlier-filed application Ser. No. 148,895 filed June 1, 1971 now U.S. Pat. No. 3,843,681 issued Oct. 22, 1974.

BACKGROUND OF THE INVENTION

This invention relates to novel indole derivatives, to processes for their preparation and to intermediates used in these processes.

Notwithstanding the advances made during the last 4 decades in the development of agents for the treatment of inflammatory conditions, there still remains a need for effective agents without the side effects associated with the therapeutic agents presently used for this purpose.

The indole derivatives of this invention have been found to exhibit interesting and useful pharmacodynamic properties without eliciting undesirable side effects. Notable attributes of this effect are antiinflammatory and analgesic activities. In addition the compounds of this invention exhibit antibacterial and antifungal properties.

SUMMARY OF THE INVENTION

The indole derivatives of this invention are characterized by having a pyrano[3,4-b]indole or thiopyrano[3,4-b]indole nucleus bearing a substituent at position 1, said substituent incorporating an acid, ester or amide function therein. These derivatives may be represented by formula I ##SPC1##

in which R¹ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl and 2-thienyl, R², R³, R⁴ and R⁵ are the same or different and are each selected from the group consisting of hydrogen and lower alkyl, R⁶ is selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro and halo, R⁷ is selected from the group consisting of hydrogen, lower alkyl and lower akenyl, X is selected from the group consisting of oxy and thio, Y is selected from the group consisting of carbonyl, ##EQU1## which each of R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is hydrogen or lower alkyl, and Z is selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, di(lower)alkylamino and phenylamino.

Also included within the scope of this invention are pyrano[3,4-b]indole and thiopyrano[3,4-b]indole derivatives of formula I in which R⁶ represents from one to four substituents, which may be present simultaneously, at positions 5,6,7 and 8 thereof. The exact nature of such substituents does not have to be limited necessarily by the above definitions of R⁶, and R⁶ may also include additional definitions, for example, mercapto, lower alkylthio, trifluoromethyl and other halo(lower)alkyls, amino and sulfamoyl, provided that any two such substituents do not interfere with each others presence. Accordingly the indole derivatives of this invention are represented also by general formula Ia ##SPC2##

in which R¹, R², R³, R⁴, R⁵, R⁷, X, Y and Z are as defined in the first instance and R^(6a), R^(6b), R^(6c) and R^(6d) are the same or different and each is selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro, halo, mercapto, lower alkylthio, trifluoromethyl, amino and sulfamoyl.

The indole derivatives of this invention of formula I are prepared by reacting a compound of the formula ##SPC3##

in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X' is hydroxy or mercapto with a compound of formula ##EQU2## in which R¹, Y and Z are as defined in the first instance, in the presence of an acid catalyst.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl and the like.

The term "lower alkenyl" as used herein contemplates both straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl and the like.

The term "lower alkynyl" as used herein contemplates both straight and branched chain alkynyl radicals containing from two to six carbon atoms and includes ethynyl, propargyl, 1,1-dimethylpropargyl and the like.

The term "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "lower alkoxy" as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straight and branched chain alkanoyloxy radicals containing from two to six carbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.

The term "halo" as used herein contemplates halogens and includes fluorine, chlorine, bromine and iodine.

Where the term "lower" is used herein as part of the description of alkylamino and dialkylamino, it contemplates one to six carbon atoms fo each alkyl group of such a radical and includes a methylamino, n-hexylamino, dimethylamino, diethylamino and the like.

The indole derivatives of formula I in which Z is hydroxy, the acid compounds of this invention, form addition salts with suitable inorganic and organic bases. These salts possess the same activities as the parent acid compound when administered to animals and may be utilized in the same manner. Suitable bases to form these salts include, for example, the hydroxides, lower alkoxides, carbonates and bicarbonates of sodium, potassium, calcium and magnesium, as well as the bases, anmmonia, triethylamine, benzylamine and the like. The addition salts thus obtained are the functional equivalents of the parent acid compound in respect to their therapeutic use. Hence, these addition salts are included within the scope of this invention and are limited only by the requirement that the bases employed in forming the salts be pharmaceutically acceptable.

Also included within the scope of this invention are the isomers of the compounds of formula I resulting from the asymmetric centers contained therein.

ANTIINFLAMMATORY AND ANALGESIC ACTIVITY

The useful antiinflammatory and analgesic activities of the indole derivatives of this invention may be demonstrated in standard pharmacologic tests, for example, the tests described by R. A. Turner in "Screening Methods in Pharmacology", Academic Press, New York and London, 1965, pp. 152-163 and pp. 100-117, respectively.

More particularly, the antiinflammatory activity of the compounds of this invention may be readily demonstrated in a modification of the Freund's adjuvant test, the adjuvant induced acute edema test as described by J. R. Boissier, et al., Therapie, 25, 43 (1970). This test is known to correlate well with data derived from clinical results with humans. Boissier et al. have demonstrated this correlation with such clinically active compounds as phenylbutazone, mefenamic acid, indomethacin, aspirin, hydrocortisone and prednisolone.

More particularly exemplified, a substantial antiinflammatory effect for the compounds listed below is demonstrable at oral doses of 100 mg/kg or less in this acute edema test. In this test male rats are treated with the test compound one hour before the injection of Freund's adjuvant into the paw (day 0). The rats are then treated with the same dose of the test compound for the next three days. The antiinflammatory effect of the test compound is measured by the reduction of pedal inflammation, see Turner cited above, and expressed as a percent inhibition from adjuvant injected control rats on day 3.

    __________________________________________________________________________                                DAILY                                                                          DOSE  PERCENT                                                COMPOUND          (MG/KG)                                                                              INHIBITION                                    __________________________________________________________________________     1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                      indole-1-acetic acid, Example No. 1                                                                       100   30                                            1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                       indole-1-acetic acid, Example No. 15                                                                      100   47                                            1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                      indole-1-acetic acid, Example No. 16                                                                      100   40                                            8-methyl-1-propyl-1,3,4,9-tetrahydropyrano-                                    [3,4-b]indole-1-acetic acid, Example No. 26                                                               100   44                                            1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                       indole-1-acetic acid, Example No. 25                                                                      100   40                                            1-t-butyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                     indole-1-acetic acid, Example No. 24                                                                      100   30                                            5-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]-                             indole-1-acetic acid, Example 32                                                                          100   44                                            1-ethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-                             1-acetic acid, Example No. 98                                                                              25   32                                            __________________________________________________________________________

The lack of side effects for the compounds of this invention may be demonstrated by standard acute toxicity tests (see Turner cited above) and by prolonged administration of the compound to warm-blooded animals.

When the present indole derivatives of this invention are employed as antiinflammatory and analgetic agents in warm-blooded animals, e.g., rats, they may be administered orally, alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically acceptable excipients, such as starch, milk sugar and so forth. They may also be administered orally in the form of solutions in suitable vehicles such as vegetable oils.

The dosage of the indole derivatives of this invention will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords protective effects without any deleterious side effects. These antiinflammatory-analgesically effective concentration levels are usually obtained within a therapeutic range of 1.0 mg to 500 mg/kg per day, with a preferred range of 10 to 100 mg/kg per day.

ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY

The indole derivatives of this invention also exhibit utility as antibacterial agents against a number of gram-positive and gram-negative microorganisms, such as, Staphylococcus pyogenes, both penicillin sensitive and penicillin resistant, Streptococcus faecalis, Escherichia coli, Aerobacter aerogenes, Salmonella pullorum, Pseudomonas aerugenosa, Proteus mirabilis, Proteus vulgaris, Klebsiella pneumoniae and Serratia marcescens and as antifungal agents against a number of pathogenic fungi such as, Candida albicans, Microsporum gypseum and Trichophyton granulosum, in standard tests for antibacterial and antifungal activity, such as those described in "Antiseptics, Disinfectants, Fungicides and Sterilization", G. F. Reddish, Ed., 2nd ed., Lea and Febiger, Philadelphia, 1957 or by D. C. Grove and W. A. Randall in "Assay Methods of Antibiotics", Med. Encycl. Inc., New York, 1955.

For example, by employing a test like the serial broth dilution, see Grove and Randall, cited above, in which dilutions of the compounds of this invention in nutrient broth are inoculated with the microorganisms or fungi, described above, incubated at 37°C. for 2 days, respectively, and examined for the presence of growth, it may be shown that 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-propionic acid is able to inhibit growth totally in this system of Proteus vulgaris, Klebsiella pneumoniae and Serratia marcescens at a concentration of 100 mcg/ml. or less.

When the compounds of this invention are employed as antibiotic or antifungal agents in warm-blooded animals, e.g. rats, they may be administered alone or in combination with pharmacologically acceptable carriers. The proportion of the compound is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents as antibiotic or antifungal agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford antibacterially or antifungally effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 1.0 mg. to about 1000 mg. per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 10 mg. to about 500 mg. per kilo per day is most desirably employed in order to achieve effective results.

In addition, the agent may be employed topically. For topical application they may be formulated in the form of solutions, creams, or lotions in pharmaceutically acceptable vehicles containing 0.1-5 per cent, preferably 2 per cent, of the agent and may be administered topically to the infected area of the skin.

Also the antibacterial properties of the compounds of this invention may be utilized for washing equipment in hospitals, homes and farms, instruments used in medicine and bacteriology, clothing used in bacteriological laboratories, and floors, walls and ceiling in rooms in which a background free of gram-positive and gram-negative microorganisms, such as those listed above, is desired. When employed in this manner the compounds of this invention may be formulated in a number of compositions comprising the active compound and an inert material. In such compositions, while the compounds of formula I of this invention may be employed in concentrations as low as 500 p.p.m., from a practical point of view, it is desirable to use from about 0.10% by weight, to about 5% by weight or more.

The formulations that may be used to prepare antiseptic wash solutions of the compounds of this invention are varied and may readily be accomplished by standard techniques, see for example, "Remington's Practice of Pharmacy", E. W. Martin et al., Eds., 12th ed., Mack Publishing Company, Easton, Penn., 1961, pp. 1121-1150. In general, the compounds may be made up in stock solutions. They can also be formulated as suspensions in an aqueous vehicle. These make useful mixtures for decontaminating premises. Also, aqueous vehicles containing emulsifying agents, such as sodium lauryl sulfate, and relatively high concentrations, e.g., up to about 5% by weight, of the compounds may be formulated by conventional techniques.

A typical antiseptic preparation useful for disinfecting floors, walls, ceiling, and articles in a contaminated room may be prepared by adding 5 to 25 g. of N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide to a mixture of 150 to 300 g. of polyethylene glycol 1540 and 150 to 300 g. of polyethylene glycol 300. The resulting mixture is stirred while a solution of 1 to 10 g. of sodium lauryl sulfate in 300 to 400 ml. of water is added portionwise. The article to be disinfected is coated or immersed in the preparation for a prolonged time, for example, one hour, and then rinsed with sterile water.

PREPARATION OF INDOLE DERIVATIVES

For the preparation of the indole derivatives of this invention we prefer to use as starting materials the compounds of the general formula II. ##SPC4##

in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X' is hydroxy or mercapto.

The starting materials of formula II in which X' is hydroxy are either known, for example, tryptophol, described by H. R. Snyder and F. J. Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948), or they may be obtained by the following process: ##EQU3##

The reference to this process phenylhydrazines of formula III and the hydroxyaldehyde of formula IV are reacted together according to the conditions of the "Fischer Indole Synthesis", for example, see P. L. Julian, E. N. Myer and H. C. Printy, "Heterocylic Compounds", R. C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp. 8-11, to form the desired starting material (II, X' = OH).

The phenylhydrazines of formula III are either known or may be prepared according to known methods. A convenient method involves the diazotization of the appropriately substituted aniline to give the corresponding diazo derivative. The latter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, see L. F. Fieser and M. Fieser, "Advanced Organic Chemistry", Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example, "Rodd's Chemistry of Carbon Compounds," S. Coffey, Ed., Vol. I d, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 44-49, or they may be prepared according to known methods. A convenient method involves reduction of an appropriate lactone of formula

    O=CH.sub.2 C(R.sup.4)(R.sup.5)C(R.sup.2)(R.sup.3)--O

with bis-(3-methyl-2-butyl)borane, H. C. Brown and D. B. Bigley, J. Am. Chem. Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. I. Zakharkkin and I. M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminum hydride, L. I. Zakharkin et al., Tetrahedron Letters, 2087 (1963). The appropriate lactones utilized in this condensation are either commercially available, for example, δ-valerolactone, α-methyl-butyrolactone, or they are described with a variety of methods for their preparation in organic chemistry textbooks; such as the textbooks, "Methoden der Organischen Chemie", Houben-Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561-852 or L. F. Fieser and M. Fieser, "Advanced Organic Chemistry", cited above.

Alternatively, the starting materials of formula II in which R², R³, R⁴ and R⁷ are hydrogen and X' is hydroxy may be prepared by lithium aluminum hydride reduction, N. G. Gaylord, "Reduction with Complex Metal Hydrides", Interscience Publishers, Inc., New York, 1956, pp. 322-370, of compounds of formula V described by T. Y. Shen, U.S. Pat. No. 3,161,654, Dec. 15, 1964: ##SPC5##

wherein R¹⁵ is lower alkyl and R⁵ and R⁶ are as defined in the first instance.

The starting materials of formula II in which X' is mercapto and R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the first instance may be obtained by the following process: The appropriate compound of formula II (X' = OH), described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or carbon tetrachloride, to afford the corresponding 3-(2-bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula II (X' = SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyanov, Khim.-Farm. Zh., 1,4 (1967), [Chem. Abstr. 67, 73474a (1967)], for converting 3-(2-bromoethyl)-indole to indole-3-ethanethiol (II; R², R³, R⁴, R⁵, R⁶ and R⁷ = H and X' = SH). Accordingly, the appropriate 3-(2-bromoethyl)indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indolyl)ethyl thiosulfate derivative, respectively, which on treatment with strong alkali for example, sodium or potassium hydroxide, is transformed into the corresponding bis-[ω-(3-indolyl)ethyl]disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II.

It should be noted that the preceding process is not entirely practical for the preparation of the compounds of formula II in which X' is mercapto and R⁶ is hydroxy or lower alkanoyloxy. For this reason, the preferred starting materials of formula II for the ultimate preparation of the compounds of formula I in which R⁶ is hydroxy or lower alkanoyloxy and X is thio are the corresponding compounds of formula II in which R⁶ is benzyloxy, readily prepared by this process. When the latter compounds are used as starting materials in this manner, they are first subjected to the process (II + VI→VII), described below. Subsequently, the benzyloxy group is removed by hydrogenation, in the presence of a catalyst, for example, 10% palladium on carbon, to afford the corresponding compound of formula I in which R⁶ is hydroxy. The latter may be converted if desired to the corresponding compound of formula I in which R⁶ is lower alkanoyloxy by conventional means, for example, by treatment with the appropriate lower alkanoic anhydride preferably in the presence of pyridine. Likewise, it should be noted that similar use of starting materials of formula II in which X' is hydroxy and R⁶ is benzyloxy to obtain the corresponding compound of formula I in which R⁶ is hydroxy or lower alkanoyloxy is preferred.

For the preparation of the acid and ester compounds of this invention of formula I in which Z is hydroxy or lower alkoxy and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, we have found that the following, hitherto undisclosed process is both practical and convenient: ##SPC6## ##SPC7##

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y and Z are as defined in this instance, X' is hydroxy or mercapto and R¹⁶ is hydrogen or lower alkyl. (For convenience and clarity these particular acid and ester compounds of formula I are represented above as formula VII).

With reference to the above scheme the starting material of formula II is condensed with a ketoacid (VI, R¹⁶ = H) or a ketoester (VI, R¹⁶ = lower alkyl) in the presence of a suitable acid catalyst to yield the compounds of formula VII.

Generally comparable yields of product are obtained in this process when either the ketoacid or the corresponding ketoester is used. However, in the case where it is desired to prepare acid compounds of formula VII in which ##EQU4## and R¹⁶ is hydrogen, it is preferable with respect to yield to first condense the appropriate β-ketoester of formula VI rather than the corresponding β-ketoacid and then hydrolyze the resulting ester product to give the desired acid compound.

Moreover, in the general practise of this invention it is often more convenient to prepare the acid compounds of formula VII by usng the ketoester instead of the ketoacid in this process and then hydrolyze the resulting ester product to the desired acid, the reason being simply that the ketoesters are generally more readily available either commercially or by synthesis.

The hydrolysis of compounds of formula VII in which R¹⁶ is lower alkyl to their corresponding acids of formula VII is readily effected by treatment with a suitable alkali, for example, potassium hydroxide or sodium carbonate, in aqueous methanol or aqueous ethanol.

In practising the condensation (II + VI→VII) we have found it preferable to use a solvent as a reaction medium. Any solvent inert to the reaction conditions may be used. Suitable solvents include benzene, toluene, diethyl ether, dioxan, tetrahydrofuran, methylene dichloride, carbon tetrachloride and the like. Benzene and tetrahydrofuran are especially convenient and practical for this use. A variety of suitable acid catalysts may be used for this condensation, for example, the type of catalyst used in a Fischer Indole Synthesis, i.e. p-toluenesulfonic acid, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid and sulfuric acid and the like. p-Toluenesulfonic acid, boron trifluoride and phosphorus pentoxide are included among the preferred acid catalysts. The amount of acid catalyst used is not especially critical and may range from 0.01 molar equivalents to 100 molar equivalents; however, a range of from 0.1 to 10 molar equivalents is generally preferred. The time of the reaction may range from 10 minutes to 60 hours, with the preferred range being from one-half to 24 hours. The temperature of the reaction may range from -20°C. to the boiling point of the reaction mixture. Preferred temperature ranges include 20° to 120°C.

The α-, β-, γ- and δ-ketoacids and -ketoesters of formula VI are either known, for example, ethyl pyruvate, levulinic acid, ethyl α,α -dimethylacetoacetate, β,β-dimethyllevulic acid and benzoylacetic acid or they may be prepared by known methods described in general organic chemistry textbooks. For example, a comprehensive review on the properties and preparation of such α-, β-, γ- and δ-ketoacids and -ketoesters may be found in "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1d, pp. 226-274.

Alternatively, the acid compounds of formula I in which Z is hydroxy and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance may be prepared by the following process: ##SPC8##

in which Y' is CH₂, C(R⁸)(R⁹)CH₂, C(R⁸)(R⁹)C(R¹⁰)(R¹¹)CH₂ or C(R⁸)R⁹)C(R¹⁰)(R¹¹)C(R¹²)(R¹³)CH₂, R¹⁷ is hydrogen or lower alkyl, Z is hydroxy and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance.

With reference to this alternative process a starting material of formula II is condensed with a ketoalcohol lower alkyl ester (VIII) in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II + VI→VII). The ketoalcohol lower alkyl esters are either known, for example, acetonyl acetate or 5-acetoxypentan-2-one, or may be prepared by known methods, for instance, see "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1d, pp. 49-54. In this manner the condensation product of general formula IX is obtained. Hydrolysis of this product with an aqueous alcoholic solution of a suitable alkali, for example, sodium hydroxide in aqueous methanol, affords the corresponding primary alcohol X. The primary alcohol is then oxidized to the corresponding aldehyde of formula XI. Although a variety of methods are known for the oxidation of a primary alcohol to its corresponding aldehyde, see for example, "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1c, pp. 4-10, we have found that the method of K. E. Pfitzner and J. G. Moffat, J. Am. Chem. Soc., 87, 5670 (1965) using N,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of a suitable acid, for example, trifluoroacetic acid, to be both efficacious and convenient in this case. Subsequently the aldehyde XI may be converted to the desired acid compounds of formula I by a variety of oxidizing agents, including silver oxide, alkaline permanganate, hydrogen peroxide, peracids and the like. In this case we prefer to use silver oxide according to the method of M. Delepine and P. Bonnet, Compt. rend., 149,39 (1909).

The amide compound of this invention of formula I in which Z is amino, lower alkylamino, di(lower)alkylamino and phenylamino and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, may be prepared from their corresponding acid compounds of formula I (compounds of formula VII in which R¹⁶ is hydrogen, described above) by treatment of the latter compounds with a lower alkyl chloroformate, preferably ethyl chloroformate, in the presence of triethylamine, affording the corresponding mixed anhydride, which is converted by treatment with the appropriate amine, such as ammonia, aniline or a suitable alkylamine or dialkylamine, to the desired amide compound of formula I.

Alternatively, these amides of formula I may be prepared from the corresponding esters of formula I (compounds of formulae VII, in which R¹⁶ is lower alkyl, described above) by treatment of the latter compounds with the appropriate amine according to known methods, for example, see A. L. J. Beckwith in "The Chemistry of Amides", J. Zalicky, Ed., Interscience Publishers, New York, 1970, pp. 96-105.

Again alternatively, the amide compounds of formula I in which Z is amino, lower alkylamino, di(lower)alkylamino, and phenylamino and R¹, R² R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, may be prepared by the condensation of an appropriate starting material of formula II with an appropriate α-, β-, γ- or δ-ketoamide in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II + VI→VII). The ketoamides required for this condensation are either known, for example, pyruvamide or α,α-dimethylacetoacetamide, or they may be prepared by known methods, for instance, see "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1d, pp. 226-274.

The alkylated acid and ester compounds of the invention of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is hydroxy or lower alkoxy, are prepared readily from the above described, corresponding acid or ester compounds of formula I in which R⁷ is hydrogen. This conversion involving the N-alkylation of the indolic nitrogen is effected by treatment of the latter compounds with an appropriate lower alkyl or lower alkenyl halide in an inert solvent in the presence of an acid acceptor. Preferred conditions for effecting this conversion include the use of sodium hydride as an acid acceptor and tetrahydrofuran as the inert solvent.

The N-alkylated amide compounds of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is amino, lower alkylamino, di(lower)alkylamino or phenylamino are preferably prepared by either treatment of the N-alkylated acid compounds of formula I, described above, with a lower alkyl chloroformate followed by treatment with the appropriate amine, or treatment of the N-alkylated ester compounds of formula I, described above, with an appropriate amine, in the manner described previously for the preparation of the amide compounds of formula I in which R⁷ is hydrogen.

Finally, it is the intention to cover all changes and modifications of the embodiment of the invention herein chosen for the purpose of disclosure which are within the scope and spirit of this invention. Such changes and modifications include those variations which depend on well known interconversions of acids and esters or alternation of the order of N-alkylation in the processes disclosed herein.

For example, in preparing the N-alkylated acid, ester or amide compounds of formula I in which R⁷ is lower alkyl or lower alkenyl, the changing of the order of the N-alkylation step, as depicted in the embodiment of this invention, by the act of N-alkylation of the starting materials of formula II and subjecting the products thereof to treatment with an appropriate ketoacid or ketoester of formula VI or a ketoamide, according to the teaching of the present disclosure, would not depart from the spirit or scope of this invention.

Likewise, the preparation of the N-alkylated amide compounds of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is di(lower)alkylamino by N-alkylation of the corresponding compounds of formula I in which R⁷ is hydrogen, is considered to be a process which would be functionally equivalent to the process embodied herein for the preparation of these compounds.

It will also be apparent to those skilled in the art that the processes taught herein for the preparation of the indole derivatives of formula I are applicable likewise to the preparation of the indole derivatives of formula Ia, described above. In the latter case, the appropriate starting material of formula IIa, see below, prepared analogously to the starting material of formula II, is utilized.

More specifically, the acid and ester compounds of formula Ia in which R^(6a), R^(6b) R^(6c) R^(6d) and R⁷ are as defined in the first instance, Z is hydroxy or lower alkoxy, and R¹, R² R³ R⁴, R⁵ X and Y are as defined in the first instance, are readily prepared by the condensation (IIa+VI→VIIa), illustrated below, according to the conditions described previously for the condensation (II+VI→VII). ##SPC9## ##SPC10##

in which R¹, R², R³, R⁴, R⁵ R^(6a), R^(6b), R^(6c), R^(6d), R⁷ X, Y and R¹⁶ are as defined in the first instance.

Likewise, the acid compounds of formula Ia in which R^(6a), R^(6b), R^(6c), R^(6d) are as defined in the first instance, Z is hydroxy and R¹, R², R³, R⁴, R⁵, R⁷, X and Y are as defined in the first instance may be prepared by the following process: ##SPC11##

in which R¹, R², R³, R⁴, R⁵, X, Y, Y', R^(6a), R^(6b), R^(6c), R^(6d), R⁷, and R¹⁷ are as defined in the first instance according to the process disclosed above for the conversion {II+VIII→IX→X→XI→I (Z = OH)}. Subsequent transformation of the above acid and ester compounds of formula Ia to their corresponding N-alkylated and amide derivatives of formula Ia is effected in the same manner for the similar conversions of the acid ester compounds of formula I, described herein.

Alternatively, the amide derivatives of formula Ia are prepared by the condensation of an appropriate starting material of formula IIa with an appropriate α-, β-, γ- or δ-ketoamide in the presence of a suitable acid catalyst according to the conditions described previously for the condensation (II + VI→VII).

The following examples will illustrate further this invention.

EXAMPLE 1 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, Y = CH₂ CO AND Z = OH)

Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid ethyl ester, as an oil, γ_(max) ^(CHCl).sbsp.3 1715 cm⁻ ¹.

Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOH in 30 ml. of H₂ O and the solution is allowed to stand ar room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HCl, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzene containing a trace of petroleum ether to afford the title compound, m.p. 150°-152°C., γ_(max) ^(CHCl).sbsp.3 3325 and 1705 cm⁻ ¹.

An equivalent amount of methyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-acetic acid methyl ester, m.p. 87°-90°C. after recrystallization from benzene-hexane, is obtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid propyl ester is obtained as the ester.

EXAMPLE 2 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-PROPIONIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, Y = CH₂ CH₂ CO AND Z = OH)

A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for 15 minutes and then at 70°C. for 1 1/2 hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOH; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na₂ SO₄) and evaporated to dryness. The residue is crystallized from ethyl acetate-petroleum ether to afford the title compound, m.p. 104°-110°C., nmr (CDCl₃) δ1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1.H).

The above title compound is also obtained by following the procedure of Example 1 but replacing ethyl acetoacetate with an equivalent amount of ethyl levulinate. In this case 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethyl ester, m.p. 116°-118°C., γ_(max) ^(CHCl) .sbsp.3 1716 cm.sup.⁻¹, after crystallization from benzene-petroleum ether, is obtained as the ester prior to hydrolysis.

EXAMPLE 3 1-METHYL-1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = S, Y = CH₂ CO AND Z = OH)

Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70°-80°C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with a 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as the semi-solid, γ_(max) ^(CHCl).sbsp.3 1715 cm.sup.⁻¹.

This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Example 1 and 2 to afford the title compound, m.p. 147°-149°C., nmr (CDCl₃) δ1.86 (S, 3H), 3.06 and 8.12 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization from benzene-hexane.

The procedures of Examples 1, or 3 may be followed to prepare other compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, X and Y are as defined in the first instance, R⁷ is hydrogen and Z is hydroxy. Examples of such compounds of formula I are listed Tables I and II. In each of these examples an equivalent amount of the starting material of formula II listed therein is used instead of the starting material of formula II described in the procedures of Examples 1 and 3. Note that in each of these examples the ester obtained prior to hydrolysis is the corresponding ester compound of formula I in which Z is a lower alkoxy of the product listed therein, the alkyl portion of said lower alkoxy being derived from the R¹⁶ portion of the ketoester of formula VI employed therein.

Similarly, the procedure of Example 2 may be used to prepare the products listed in Tables I and II. In this case an equivalent amount of the starting material of formula II, listed therein is used instead of the starting material of formula II described in Example 2 and an equivalent amount of the corresponding ketoacid of formula VI of the ketoester of formula VI listed therein is used instead of the said ketoester.

                                      TABLE I                                      __________________________________________________________________________                                    KETOESTER OF     PRODUCT: [(PREFIX                                             FORMULA VI       LISTED BELOW)-1,3,4,9-                                        O                TETRAHYDROPYRANO-              Ex.                                                                               STARTING MATERIAL OF        ∥       [3,4-b]INDOLE-1-                  FORMULA II                  (R.sup.1 --C--Y--OR.sup.16)                                                                     (SUFFIX LISTED BELOW)]            R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                              X R.sup.1                                                                               Y              R.sup.16                                                                          PREFIX//SUFFIX                 __________________________________________________________________________     4  H  H  H  H  H     O CH.sub.3                                                                              CO             C.sub.2 H.sub.5                                                                   1-methyl//carboxylic                                                           acid                           5  CH.sub.3                                                                          H  H  H  H     O C.sub.2 H.sub.5                                                                       CO             C.sub.2 H.sub.5                                                                   1-ethyl-3-methyl//                                                             carboxylic acid                6  n- H  H  H  5-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                     CO             CH.sub.3                                                                          1,3-diisopropyl-6-                C.sub.3 H.sub.7                              methyl//carboxylic                                                             Acid                           7  CH.sub.3                                                                          CH.sub.3                                                                          H  H  5-OH  O CH.sub.3 CH=CH                                                                        CO             CH.sub.3                                                                          3,3-dimethyl-6-hydroxy                                                         1-(1-propenyl)//                                                               carboxylic acid                8  H  H  H  H  7-C.sub.2 H.sub.5                                                                    O HC.tbd.C                                                                              CO             CH.sub.3                                                                          8-ethyl-1-ethynyl//                                                            carboxylic acid                9  H  H  2- H  H     O        CO             CH.sub.3                                                                          1-cyclopropyl-4-isopro-                 C.sub.3 H.sub.7                        pyl//carboxylic acid           10 CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H     O        CO             CH.sub.3                                                                          1-cyclopentyl-4,4-                                                             diethyl-3,3-dimethyl//                                                         carboxylic acid                11 H  H  H  H  H     O        CO             CH.sub.3                                                                          1-phenyl//carboxylic                                                           acid                           12 CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   H  H  H     O        CO             CH.sub.3                                                                          1-benzyl-3-ethyl-                                                              3-methyl//carboxylic                                                           acid                           13 H  H  H  H  6-Cl  O        CO                7-chloro-1-(2-                                                                 thienyl)//carboxylic                                                           acid                           14 H  H  CH.sub.3                                                                          H  H     O CH.sub.3                                                                              CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1,4-dimethyl//acetic                                                           acid m.p. 163-164              15 H  H  H  H  H     O C.sub.2 H.sub.5                                                                       CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-ethyl//acetic acid                                                           m.p. 137-140°C.         16 H  H  H  H  H     O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-propyl//acetic acid                                                          m.p. 148-151°C          __________________________________________________________________________                                                     PRODUCT:[(PREFIX                                      KETOESTER OF             LISTED BELOW)-1,3,4,9-                                FORMULA VI               TETRAHYDROPYRANO-              EX.                                                                               STARTING MATERIAL OF                         [3,4-b]INDOLE-1-                  FORMULA II          (R.sup.1 --CO--Y--OR.sup.16)                                                                            (SUFFIX LISTED BELOW)]            R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                              X R.sup.1                                                                               Y              R.sup.16                                                                          PREFIX//SUFFIX                 __________________________________________________________________________     17 H  H  H  H  H     O i-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-isopropyl//acetic                                                            acid, m.p.                                                                     150-152°C.              18 CH.sub.3                                                                          H  H  H  H     O CH.sub.2 =CHCH.sub.2                                                                  CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-allyl-3-methyl//                                                             acetic acid                    19 CH.sub.3                                                                          H  H  H  H     O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   3-methyl-1-propyl//                                                            acetic acid;                                                                   m.p. 75- 80°C.                                                          (Isomer A),m.p. 146-                                                           148°C (Isomer B).       20 CH.sub.3                                                                          H  C.sub.2 H.sub.5                                                                   CH.sub.3                                                                          H     O HC.tbd.C                                                                              CH.sub.2 CO    C.sub.2 H.sub.5                                                                   4-ethyl-1-ethynyl-3-                                                           methyl//acetic acid,                                                           -          ν.sub.max                                                        CHCl.sub.3                                                                     3300,2135,1710cm.sup..sup.                                                     -1                             21 H  H  H  H  H     O CH.sub.3                                                                              CH(CH.sub.3)CO C.sub.2 H.sub.5                                                                   α,1-dimethyl//acetic                                                     c                                                                              acid; m.p.                                                                     154-156°C.                                                              (Isomer A), m.p. 163-                                                          165°C. (Isomer                                                          B).                            22 H  H  H  H  H     O        C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   1-cyclohexyl-α,.alph                                                     a.-                                                                            dimethyl//acetic acid          23 H  H  H  H  H     O        CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-phenyl//acetic acid,                                                         m.p. 148-150°C.         24 H  H  H  H  H     O t-C.sub.4 H.sub.9                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-t-butyl//acetic acid,                                                        m.p. 210-212°C.         25 H  H  H  H  H     O n-C.sub.4 H.sub.9                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-butyl//acetic acid                                                           m.p. 124-127°C          26 H  H  H  H  7-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   8-methyl-l-propyl//                                                            acetic acid m.p. 127-                                                          128°C                   27 H  H  H  H  H     O        CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-(2-thienyl)//acetic                                                          acid m.p.                                                                      127-130°C.              28 H  H  H  H  5-Br  O C.sub.2 H.sub.5                                                                       CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-bromo-1-ethyl//acetic                                                        acid m.p.                                                                      182-184°C.              29 H  H  H  H  5-OCH.sub.3                                                                          O CH.sub.3                                                                              CH.sub.2 CO    CH.sub.3                                                                          6-methoxy-1-methyl//                                                           acetic acid, m.p.                                                              142-143°C.              30 H  H  H  H  5-OCOCH.sub.3                                                                        O CH.sub.3                                                                              CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-acetoxy-1-methyl//                                                           acetic acid, m.p.                                                              142-143°C.              31 H  H  H  H  5-benzyl-                                                                            O CH.sub.3                                                                              CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-benzyloxy-1-methyl//                        oxy                              acetic acid, m.p.                                                              163.5°C.                32 H  H  H  H  4-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   5-methyl-1-propyl//                                                            acetic acid, m.p.                                                              177-178°C.              33 H  H  H  H  6-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   7-methyl-1-propyl//                                                            acetic acid, m.p.                                                              157-158°C.              34 H  H  H  H  5-NO.sub.2                                                                           O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-nitro-1-propyl//                                                             acetic acid,m.p.119-                                                           120°C.                  35 i- H  i- H  5-NO.sub.2                                                                           O CH.sub.2 =CH                                                                          CH(CH.sub.3)CO C.sub.2 H.sub.5                                                                   3,4-diisopropyl-α-          C.sub.3 H.sub.7                                                                      C.sub.3 H.sub.7                        methyl-6-nitro-1-                                                              vinyl//acetic acid             36 H  H  CH.sub.3                                                                          CH.sub.3                                                                          H     O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   4,4-dimethyl-1-                                                                propyl//acetic acid,                                                           m.p. 184-185°C.         37 H  H  C.sub.2 H.sub.5                                                                   H  7-CH.sub.3                                                                           O HC.tbd.C                                                                              C(i-C.sub.3 H.sub.7).sub.2 CO                                                                 C.sub.2 H.sub.5                                                                   α,α-diisopropy                                                     l-4-                                                                           ethyl-1-ethynyl-8-                                                             methyl//acetic acid            38 CH.sub.3                                                                          CH.sub.3                                                                          H  H  5-OC.sub.2 H.sub.5                                                                   O        CH(C.sub.2 H.sub.5)CO                                                                         C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.alp                                                     ha.-                                                                           diethyl-3,3-dimethyl-                                                          6-ethoxy//acetic acid          39 CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-C.sub.2 H.sub.5                                                                    O        C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   1-cyclohexyl-α,.alph                                                     a.,3,3-                                                                        tetramethyl-4,4,7-                                                             triethyl//acetic acid          40 CH.sub.3                                                                          H  n- n- 4-n-C.sub.3 H.sub.7                                                                  O        CH(CH.sub.3)CO C.sub.2 H.sub.5                                                                   α,3-dimethyl-1-pheny                                                     l                                                                              4,4,5-tripropyl//                                                              acetic acid                    41 H  H  H  H  H     O        C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   α,α-dimethyl-1                                                     -phenyl//                                                                      acetic acid                    42 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   4-C.sub.2 H.sub.5                                                                    O        C(i-C.sub.3 H.sub.7).sub.2 CO                                                                 C.sub.2 H.sub.5                                                                   1-benzyl-α,α-                                                      diisopropyl-3,3,4,4,5-                                                         pentaethyl//acetic                                                             acid                                          O                                                                              ∥                                                      43 CH.sub.3                                                                          H  H  H  7-OCC.sub.2 H.sub.5                                                                  O        C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   1-benzyl-8-propionoxy-                                                         α,α,3-trimethy                                                     l//                                                                            acetic acid                    44 H  H  CH.sub.3                                                                          H  H     O        CH(CH.sub.3)CO C.sub.2 H.sub.5                                                                   α,4-dimethyl-1-                                                          (2-thienyl)//acetic                                                            acid                           45 H  H  H  H  H     O        C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   α,α-dimethyl-1                                                     -                                                                              (2-thienyl)//acetic                                                            acid                           46 H  H  H  H  4-I   O i-C.sub.3 H.sub.7                                                                     CH.sub.2 CH.sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   5-iodo-1-isopropyl//                                                           propionic acid                                O                                                                              ∥                       8-acetoxy-α,3,3,4,4-     47 CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          7-OCCH.sub.3                                                                         O CH.sub.2 =CH                                                                          CH.sub.2 CH(CH.sub.3)CO                                                                       C.sub.2 H.sub.5                                                                   pentamethyl-1-vinyl//                                                          propionic acid                 48 H  H  H  H  6-OH  O HC.tbd.C-CH.sub.2                                                                     CH.sub.2 C(C.sub.2 H.sub.5).sub.2 CO                                                          C.sub.2 H.sub.5                                                                   β,β-diethyl-7-hy                                                     droxy-                                                                         1-(2-propynyl)//                                                               propionic acid                 49 CH.sub.3                                                                          H  H  H  7-NO.sub.2                                                                           O        CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                   1-cyclobutyl-3-methyl-                                                         8-nitro-α-propyl//                                                       propionic acid                 50 H  H  CH.sub.3                                                                          H  5-CH.sub.3                                                                           O        C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                           C.sub.2 H.sub.5                                                                   α,α,β,.be                                                     ta.,4,6-hexamethyl                                                             1-phenyl//propionic                                                            acid                           51 i- H  H  H  7-Br  O        CH(CH.sub.3)CH(C.sub.2 H.sub.5)CO                                                             C.sub.2 H.sub.5                                                                   1-benzyl-8-bromo-α-         C.sub.3 H.sub.7                              ethyl-3-isopropyl-β-                                                      methyl//propionic                                                              acid                           52 C.sub.2 H.sub.5                                                                   H  C.sub.2 H.sub.5                                                                   H  7-Cl  O        CH.sub.2 CH.sub.2 CO                                                                          C.sub.2 H.sub.                                                                    8-chloro-3,4-diethyl-                                                          1-(2-thienyl)//                                                                propionic acid                 53 CH.sub.3                                                                          H  H  H  H     O CH.sub.3                                                                              CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                           C.sub.2 H.sub.5                                                                   1,3-dimethyl-α,.alph                                                     a.-                                                                            dipropyl//propionic                                                            acid                           54 CH.sub.3                                                                          H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H     O CH.sub.2 =C--CH.sub.2                                                                 CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                              CH.sub.3                                                                          4,4-diethyl-1-                                        |               methallyl-α,α,                                                     β,3-                                             CH.sub.3                 tetramethyl//                                                                  propionic acid                 55 H  H  CH.sub.3                                                                          CH.sub.3                                                                          H     O HC.tbd.C                                                                              C(CH.sub.3).sub.2 CH.sub.2 CO                                                                 CH.sub.3                                                                          1-ethynyl-β,β,4,                                                     4-                                                                             tetramethyl//propionic                                                         acid                                          O                                                                              ∥                                                      56 H  H  n- H  4-OCC.sub.2 H.sub.5                                                                  O        C(C.sub.2 H.sub.5).sub.2 C(C.sub.2 H.sub.5)C                                   O              CH.sub.3                                                                          1-cyclopentyl-5-                        C.sub.3 H.sub.7                        propionoxy-4-propyl-                                                           α,β,β-trie                                                     thyl//                                                                         propionic acid                 57 n- H  H  H  4-OCH.sub.3                                                                          O        CH.sub.2 CH(CH.sub.3)CO                                                                       C.sub.2 H.sub.5                                                                   5-methoxy-α-methyl-         C.sub.3 H.sub.7                              1-phenyl-3-propyl//                                                            propionic acid                 58 H  H  i- H  6-benzyl-                                                                            O        CH.sub.2 CH(C.sub.2 H.sub.5)CO                                                                C.sub.2 H.sub.5                                                                   1-benzyl-7-benzyloxy-                   C.sub.3 H.sub.7                                                                      oxy                              α-ethyl-4-isopropyl/                                                     /                                                                              propionic acid                 59 CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          7-Cl  O        CH(CH.sub.3)CH.sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   8-chloro-β,3,3,4,4-                                                       pentamethyl-1-                                                                 (2-thienyl)//propionic                                                         acid                           60 C.sub.2 H.sub.5                                                                   H  H  H  5-NO.sub.2                                                                           O CH.sub.3                                                                              CH(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                            H.sub.5).sub.2 CO                                                                             C.sub.2 H.sub.5                                                                   1-methyl-6-nitro-α,.                                                     alpha.-                                                                        β,β,3-pentaethyl                                                     //                                                                             propionic acid                 61 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  H  5-F   O CH.sub.2 =CHCH.sub.2                                                                  CH(C.sub.2 H.sub.5)CH(CH.sub.3)CO                                                             C.sub.2 H.sub.5                                                                   1-allyl-6-fluoro-α-                                                      N                                                                              methyl-β,3,3-triethyl                                                     //                                                                             propionic acid                 62 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  H  4-C.sub.2 H.sub.5                                                                    O CH.sub.3 C.tbd.CH                                                                     C(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                               CH.sub.3                                                                          β-propyl-1-(1-                                                            propynyl)-3,3,5-                                                               triethyl//propionic                                                            acid                           63 H  H  H  H  6-OC.sub.2 H.sub.5                                                                   O        CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                                      C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.bet                                                     a.-                                                                            diethyl-6-ethoxy//                                                             propionic acid                 64 CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          6-O-n-C.sub.3 H.sub.7                                                                O        C(CH.sub.3).sub.2 CH(CH.sub.3)CO                                                              C.sub.2 H.sub.5                                                                   α,β,β,3,3,                                                     4,4-                                                                           heptamethyl-1-phenyl-                                                          7-propoxy//propionic                                                           acid                           65 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  H  5-CH.sub.3                                                                           O        C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                           C.sub.2 H.sub.5                                                                   1-benzyl-3,3-diethyl-                                                          α,α,β,.be                                                     ta.,6-pentamethyl//                                                            propionic acid                 66 n- H  H  H  4-OH  O        C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                           C.sub.2 H.sub.5                                                                   5-hydroxy-3-propyl-               C.sub.3 H.sub.7                              α                                                                        ,α,β,β-tet                                                     ramethyl-                                                                      1-(2-thienyl)//                                                                propionic acid                 67 H  H  H  H  H     O CH.sub.3                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CO                                                                 C.sub.2 H.sub.5                                                                   1-methyl//butyric                                                              acid, m.p.                                                                     132-135°C.              68 CH.sub.3                                                                          H  H  H  H     O C.sub.2 H.sub.5                                                                       CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                   γ,3-dimethyl-1-ethyl                                                     //                                                                             butyric acid                   69 CH.sub.3                                                                          CH.sub.3                                                                          H  H  H     O n-C.sub.3 H.sub.7                                                                     C(C.sub.2 H.sub.5).sub.2 CH.sub.2 CH.sub.2                                     CO             C.sub.2 H.sub.5                                                                   γ,γ-diethyl-3,                                                     3-                                                                             dimethyl-1-propyl//                                          butyric acid                                     70 CH.sub.3                                                                          CH.sub.3                                                                          n- H  H     O CH.sub.2 =CH                                                                          C(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.3                                        H.sub.7)CH.sub.2 CO                                                                           C.sub.2 H.sub.5                                                                   3,3-dimethyl-β,.gamma                                                     .,γ,4-                            C.sub.3 H.sub.7                        tetrapropyl-1-vinyl//                                                          butyric acid                   71 H  H  H  H  H     O CH.sub.2 =CHCH.sub.2                                                                  [C(CH.sub.3).sub.2 ].sub.2 CH.sub.2                                                           C.sub.2 H.sub.5                                                                   1-allyl-β,β,.gam                                                     ma.,γ-                                                                   tetramethyl//butyric                                                           acid                           72 H  H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-Cl  O CH.sub.2 =CH--                                                                        [C(C.sub.2 H.sub.5).sub.2 ].sub.2 CH(C.sub.2                                    H.sub.5)CO    C.sub.2 H.sub.5                                                                   7-chloro-α,β,.b                                                     eta.,γ,γ,4,-                                                       4-heptaethyl-1-vinyl//                                                         butyric acid                   73 H  H  CH.sub.3                                                                          H  4-CH.sub.3                                                                           O HC.tbd.CH                                                                             [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                   1-ethynyl-α,α,                                                     β,β,γ,.gam                                                     ma.,-                                                                          4,5-octamethyl//                                                               butyric acid                                  O                                                                              ∥                                                      74 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  5-OCCH.sub.3                                                                         O CH.sub.3 C.tbd.CH                                                                     CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5)].sub.                                   2 CO           C.sub.2 H.sub.5                                                                   6-acetoxy-α,α,                                                     β,β,γ,3,-                                                      3,4-octaethyl-1-                                                               (1-propynyl)//butyric                                                          acid                           75 H  H  CH.sub.3                                                                          CH.sub.3                                                                          7-OCH.sub.3                                                                          O        CH.sub.2 [C(CH.sub.3).sub.2 ].sub.2                                                           C.sub.2 H.sub.5                                                                   1-cyclobutyl-α,.alph                                                     a.,β,β,-                                                             4,4-hexamethyl-o-                                                              methoxy//butyric acid          76 H  H  H  H  4-Br  O        CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                   5-bromo-1-cyclopentyl-                                                         α,α,β-tri                                                     methyl//                                                                       butyric acid                   77 CH.sub.3                                                                          CH.sub.3                                                                          H  H  4-n-C.sub.3 H.sub.7                                                                  O        CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                     CO             C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.alp                                                     ha.-                                                                           diethyl-3,3-dimethyl-                                                          5-propyl//butyric                                                              acid                           78 H  H  H  H  7-C.sub.2 H.sub.5                                                                    O        CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                              C.sub.2 H.sub.5                                                                   8-ethyl-α-methyl-1-                                                      phenyl//butyric acid           79 CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          H  5-F   O        [CH(CH.sub.3)].sub.3 CO                                                                       C.sub.2 H.sub.5                                                                   6-fluoro-α,β,.g                                                     amma.3,3,4-                                                                    hexamethyl-1-phenyl//                                                          butyric acid                   80 CH.sub.3                                                                          CH.sub.3                                                                          H  H  4-CH.sub.3                                                                           O        CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                         H.sub.5 )CO    C.sub.2 H.sub.5                                                                   α,γ-diethyl-1-                                                     phenyl-                                                                        3,3,5-trimethyl//                                                              butyric acid                   81 C.sub.2 H.sub.5                                                                   H  H  H  6-NO.sub.2                                                                           O        [CH(CH.sub.3)].sub.3 CO                                                                       C.sub.2 H.sub.5                                                                   1-benzyl-3-ethyl-7-                                                            nitro-α,β,.gamm                                                     a.-                                                                            trimethyl//butyric                                                             acid                           82 CH.sub.3                                                                          CH.sub.3                                                                          H  H  4-n-C.sub.3 H.sub.7                                                                  O        CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                          C.sub.2 H.sub.5                                                                   1-benzyl-α,β-di                                                     ethyl-                                                                         3,3-dimethyl-5-                                                                propyl//butyric acid           83 H  H  H  H  7-OH  O        C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).sub.2                                    CO            C.sub.2 H.sub.5                                                                   1-benzyl-8-hydroxy-                                                            α,α,γ,.g                                                     amma. -tetramethyl//                                                           butyric acid                   84 CH.sub.3                                                                          H  CH.sub.3                                                                          H  4-OC.sub. 2 H.sub.5                                                                  O        [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                   5-ethoxy-α,α,.                                                     beta.,β,γ,.gamm                                                     a.,-                                                                           3,4-octomethyl-1-                                                              (2-thienyl)//                                                                  butyric acid                   85 C.sub.2 H.sub.5                                                                   H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-Cl  O        CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                     CO             C.sub.2 H.sub.5                                                                   7-chloro-α,α,3                                                     ,4,4-                                                                          pentaethyl-1-                                                                  (2-thienyl)//                                                                  butyric acid                   86 CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          4-Br  O        CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                              C.sub.2 H.sub.5                                                                   5-bromo-α,3,3,4,4-                                                       pentamethyl-1-                                                                 (2-thienyl)//                                                                  butyric                        __________________________________________________________________________                                                     acid                      

                                      TABLE II                                     __________________________________________________________________________                                                    PRODUCT: [(PREFIX                  STARTING MATERIAL OF     KETOESTER OF       LISTED BELOW)-1,3,4,9-          EX.                                                                               FORMULA II               FORMULA VI         TETRAHYDROTHIOPYRANO-                                       O                                                                              ∥         [3,4-b]INDOLE-1-                                            (R.sup.1 --C--Y--OR.sup.16)                                                                       (SUFFIX LISTED BELOW)]             R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                              X R.sup.1  Y           R.sup.16                                                                          PREFIX//SUFFIX                  __________________________________________________________________________     87 H  H  H  H  H     S CH.sub.3 CO          C.sub.2 H.sub.5                                                                   1-methyl//carboxylic                                                           acid                            88 CH.sub.3                                                                          H  H  H  H     S C.sub.2 H.sub.5                                                                         CO          C.sub.2 H.sub.5                                                                   1-ethyl-3-methyl//                                                             carboxylic acid                 89 i- H  H  H  5-CH.sub.3                                                                           S i-C.sub.3 H.sub.7                                                                       CO          CH.sub.3                                                                          1,3-diisopropyl-6-                 C.sub.3 H.sub.7                             methyl//carboxylic                                                             acid                            90 CH.sub.3                                                                          CH.sub.3                                                                          H  H  5-OH  S CH.sub.3 CH=CH                                                                          CO          CH.sub.3                                                                          3,3-dimethyl-6-                                                                hydroxy-1-(1-propenyl)//                                                       carboxylic acid                 91 H  H  H  H  7-C.sub.2 H.sub.5                                                                    S HC.tbd.C CO          CH.sub.3                                                                          8-ethyl-1-ethynyl//                                                            carboxylic acid                 92 H  H  i- H  H     S          CO          CH.sub.3                                                                          1-cyclopropyl-4-iso-                     C.sub.3 H.sub.7                       propyl//carboxylic                                                             acid                            93 CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H     S          CO          CH.sub.3                                                                          1-cyclopentyl-4,4-                                                             diethyl-3,3-dimethyl//                                                         carboxylic acid                 94 H  H  H  H  H     S          CO          CH.sub.3                                                                          1-phenyl//carboxylic                                                           acid                            95 CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   H  H  H     S          CO          CH.sub.3                                                                          1-benzyl-3-ethyl-                                                              3-methyl//carboxylic                                                           acid                            96 H  H  H  H  6-Cl  S          CO          7-chloro-1-(2-thienyl)//                                                          carboxylic acid                 97 H  H  CH.sub.3                                                                          H H                                                                               S     CH.sub.3                                                                         CH.sub.2 CO                                                                             C.sub.2 H.sub.5                                                                            1,4-dimethyl//acetic                                                              acid                            98 H  H  H  H  H     S C.sub.2 H.sub.5                                                                         CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-ethyl//acetic acid,                                                          m.p. 138°C.              99 H  H  H  H  H     S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-propyl//acetic acid,                                                         m.p. 127- 129°C.         100                                                                               H  H  H  H  H     S i-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-isopropyl//acetic                                                            acid                            101                                                                               CH.sub.3                                                                          H  H  H  H     S CH.sub.2 =CHCH.sub.2                                                                    CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-allyl-3-methyl//                                                             acetic acid                     102                                                                               CH.sub.3                                                                          H  H  H  H     S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   3-methyl-1-propyl//                                                            acetic acid                     103                                                                               CH.sub.3                                                                          H  C.sub.2 H.sub.5                                                                   CH.sub.3                                                                          H     S HC.tbd.C CH.sub.2 CO C.sub.2 H.sub.5                                                                   4-ethyl-1-ethynyl-                                                             3-methyl//acetic                                                               acid                            104                                                                               H  H  H  H  H     S CH.sub.3 CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                   α,1-dimethyl//acetic                                                     N                                                                              acid                            105                                                                               H  H  H  H  H     S          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   1-cyclohexyl-α,.alpha                                                    .-                                                                             dimethyl//acetic                                                               acid                            106                                                                               H  H  H  H  H     S          CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-phenyl//acetic                                                               acid                            107                                                                               H  H  H  H  H     S t-C.sub.4 H.sub.9                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-t-butyl//acetic                                                              acid                            108                                                                               H  H  H  H  H     S n-C.sub. 4 H.sub.9                                                                      CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-butyl//acetic acid            109                                                                               H  H  H  H  7-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   9-methyl-1-propyl//                                                            acetic acid                     110                                                                               H  H  H  H  H     S          CH.sub.2 CO C.sub.2 H.sub.5                                                                   1-(2-thienyl)//                                                                acetic acid                     111                                                                               H  H  H  H  5-Br  S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   6-bromo-1-propyl//                                                             acetic acid                     112                                                                               H  H  H  H  5-OCH.sub.3                                                                          S CH.sub.3 CH.sub.2 CO CH.sub.3                                                                          6-methoxy-1-methyl//                                                           acetic acid                     __________________________________________________________________________                                                    PRODUCT: [PREFIX                                                               LISTED BELOW)-1,3,4,9-          EXAMPLE                                                                           STARTING MATERIAL OF                                                                               KETOESTER OF            TETRAHYDROTHIOPYRANO-              FORMULA II          FORMULA VI              [3,4-b]INDOLE-1-                                       (R.sup.1 --CO--Y--OR.sup.16)                                                                           (SUFFIX LISTED BELOW)]             R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                              X R.sup. 1 Y           R.sup.16                                                                          PREFIX//SUFFIX                  __________________________________________________________________________     113                                                                               H  H  H  H  5-OCOCH.sub.3                                                                        S CH.sub.3 CH.sub.2 CO C.sub.2 H.sub.5                                                                   6-acetoxy-1-methyl//                                                           acetic acid                     114                                                                               H  H  H  H  5-benzyl-                                                                            S CH.sub.3 CH.sub.2 CO C.sub.2 H.sub.5                                                                   6-benzyloxy-1-                                 oxy                             methyl//acetic acid             115                                                                               H  H  H  H  4-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   5-methyl-1-propyl//                                                            acetic acid                     116                                                                               H  H  H  H  6-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                   7-methyl-1-propyl//                                                            acetic acid                     117                                                                               H  H  H  H  7-F   S CH.sub.2 =CH                                                                            C(C.sub.2 H.sub.5).sub.2 CO                                                                C.sub.2 H.sub.5                                                                   α,α-diethyl-8-                                                     N                                                                              fluoro-1-vinyl//                                                               acetic acid                     118                                                                               i- H  i- H  5-NO.sub.2                                                                           S CH.sub.2 =CH                                                                            CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                   3,4-diisopropyl-α-           C.sub.3 H.sub.7                                                                      C.sub.3 H.sub.7                       methyl-6-nitro-                                                                1-vinyl//acetic                                                 acid                                           119                                                                               CH.sub.3                                                                          CH.sub.3                                                                          H  H  5-Cl  S CH.sub.3 C.tbd.C                                                                        CH(i-C.sub.3 H.sub.7)CO                                                                    C.sub.2 H.sub.5                                                                   6-chloro-3,3-dimethyl                                                          α-isopropyl-1-                                                           (1-propynyl)//acetic                                                           acid                            120                                                                               H  H  C.sub.2 H.sub.5                                                                   H  7-CH.sub.3                                                                           S HC.tbd.C C(i-C.sub.3 H.sub.7).sub.2 CO                                                              C.sub.2 H.sub.5                                                                   α,α-diisopropyl                                                    -                                                                              4-ethyl-1-ethynyl-                                                             8-methyl//acetic                                                               acid                            121                                                                               CH.sub.3                                                                          CH.sub.3                                                                          H  H  5-OC.sub.2 H.sub.5                                                                   S          CH(C.sub.2 H.sub.5)CO                                                                      C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.alph                                                    a.-                                                                            diethyl-3,3-                                                                   dimethyl-6-ethoxy//                                                            acetic acid                     122                                                                               CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-C.sub.2 H.sub.5                                                                    S          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   1-cyclohexyl-α,.alpha                                                    .,3,3-                                                                         tetramethyl-4,4,7-                                                             triethyl//acetic                                                               acid                            123                                                                               CH.sub.3                                                                          H  n- n- 4-n-C.sub.3 H.sub.7                                                                  S          CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                   α,3-dimethyl-1-phenyl                                                    -                                        C.sub.3 H.sub.7                                                                   C.sub.3 H.sub.7                 4,4,5-tripropyl//                                                                 acetic acid.                    124                                                                               H  H  H  H  H     S          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   α,α-dimethyl-1-                                                    phenyl/                                                                        acetic acid                     125                                                                               C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   4-C.sub.2 H.sub.5                                                                    S          C(i-C.sub.3 H.sub.7).sub.2 CO                                                              C.sub.2 H.sub.5                                                                   1-benzyl-α,α-                                                      diisopropyl-3,3,4,4,5-                                                         pentaethyl//acetic                                                             acid                                           O                                                                              ∥                                                      126                                                                               CH.sub.3                                                                          H  H  H  7-OCC.sub.2 H.sub.5                                                                  S          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   1-benzyl-8-propionoxy-                                                         α,α,3-trimethyl                                                    //                                                                             acetic acid                     127                                                                               H  H  CH.sub.3                                                                          H  H     S          CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                   α,4-dimethyl-1-                                                          (2-thienyl)//acetic                                                            acid                            128                                                                               H  H  H  H  H     S          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   α,α-dimethyl-1-                                                    (2-thienyl)//acetic                                                            acid                            129                                                                               H  H  H  H  H     S CH.sub.3 CH.sub.2 CH.sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   1-methyl//                                     O                               propionic acid                                 ∥                                                      130                                                                               CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          7-OCCH.sub.3                                                                         S CH.sub.2 =CH                                                                            CH.sub.2 CH(CH.sub.3)CO                                                                    C.sub.2 H.sub.5                                                                   pentamethyl-1-vinyl//                                                          propionic                       131                                                                               H  H  H  H  6-OH  S HC.tbd.C--CH.sub.2                                                                      C.sub.2 C(C.sub.2 H.sub.5).sub.2 CO                                                        C.sub.2 H.sub.5                                                                   β,β-diethyl-7-hyd                                                    roxy-                                                                          1-(2-propynyl)//                                                               propionic acid                  132                                                                               CH.sub.3                                                                          H  H  H  7-NO.sub.2                                                                           S          CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                           C.sub.2 H.sub.5                                                                   1-cyclobutyl-3-methyl-                                                         8-nitro-α-propyl//                                                       propionic acid                  133                                                                               H  H  CH.sub.3                                                                          H  5-CH.sub.3                                                                           S          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                   α,α,β,.bet                                                    a.,4,6-hexamethyl-                                                             1-phenyl//propionic                                                            acid                            134                                                                               i- H  H  H  7-Br  S          CH(CH.sub.3)CH(C.sub.2 H.sub.5)CO                                                          C.sub.2 H.sub.                                                                    1-benzyl-8-bromo-α           C.sub.3 H.sub.7                             ethyl-3-isopropyl-β                                                       methyl//propionic                                                              acid                            135                                                                               C.sub.2 H.sub.5                                                                   H  C.sub.2 H.sub.5                                                                   H  7-Cl  S          CH.sub.2 CH.sub.2 CO                                                                       C.sub.2 H.sub.5                                                                   8-chloro-3,4-diethyl-                                                          1-(2-thienyl)//                                                                propionic acid                  136                                                                               CH.sub.3                                                                          H  H  H  H     S CH.sub.3 CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                        C.sub.2 H.sub.5                                                                   1,3-dimethyl-α,.alpha                                                    .-                                                                             dipropyl//propionic                                                            acid                            137                                                                               CH.sub.3                                                                          H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H     S CH.sub.2 =C(CH.sub.3)CH.sub.2                                                           CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                           CH.sub.3                                                                          4,4-diethyl-1-                                                                 methallyl-α,α,.                                                    beta.,3-                                                                       tetramethyl//                                                                  propionic acid                  138                                                                               H  H  CH.sub.3                                                                          CH.sub.3                                                                          H     S HC.tbd.C C(CH.sub.3).sub.2 CH.sub.2 CO                                                              CH.sub.3                                                                          1-ethynyl-β,β,4,4                                                    -                                                                              tetramethyl//propionic                                                         acid                                           O                                                                              ∥                                                      139                                                                               H  H  n- H  4-OCC.sub.2 H.sub.5                                                                  S          C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5)C.  CH.sub.3                                                                          1-cyclopentyl-5-                         C.sub.3 H.sub.7                       propionoxy-4-propyl-                                                           α,β,β-triet                                                    hyl//                                                                          propionic acid                  140                                                                               n- H  H  H  4-OCH.sub.3                                                                          S          CH.sub.2 CH(CH.sub.3)CO                                                                    C.sub.2 H.sub.5                                                                   5-methoxy-α-methyl-          C.sub.3 H.sub.7                             1-phenyl-3-propyl//                                                            propionic acid                  141                                                                               H  H  i- H  6-benzyl-                                                                            S          CH.sub.2 CH(C.sub.2 H.sub.5)CO                                                             C.sub.2 H.sub.5                                                                   1-benzyl-6-benzyloxy-                    C.sub.3 H.sub.7                                                                      oxy                             α-ethyl-4-isopropyl                                                      propionic acid                  142                                                                               CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          7-Cl  S          CH(CH.sub.3)CH.sub.2 CO                                                                    C.sub.2 H.sub.5                                                                   8-chloro-β,3,3,4,4-                                                       pentamethyl-1-                                                                 (2-thienyl)//propionic                                                         acid                            143                                                                               C.sub.2 H.sub.5                                                                   H  H  H  5-NO.sub.2                                                                           S CH.sub.3 CH(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                            H.sub.5).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   1-methyl-6-nitro-α,.a                                                    lpha.                                                                          β,β,3-pentaethyl/                                                    /                                                                              propionic acid                  144                                                                               C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  H  5-F   S CH.sub.2 =CHCH.sub.2                                                                    CH(C.sub.2 H.sub.5)CH(CH.sub.3)CO                                                          C.sub.2 H.sub.5                                                                   1-allyl-6-fluoro-α-                                                      methyl-β,3,3-triethyl/                                                    /                                                                              propionic acid                  145                                                                               C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  H  4-C.sub.2 H.sub.5                                                                    S CH.sub.3 C.tbd.CH                                                                       C(n-C.sub. 3 H.sub.7)CH.sub.2 CO                                                           CH.sub.3                                                                          β-propyl-1-(1-                                                            propynyl)-3,3,5-                                                               triethyl//propionic                                                            acid                            146                                                                               H  H  H  H  6-OC.sub.2 H.sub.5                                                                   S          CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                                   C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.beta                                                    .-                                                                             diethyl-6-ethoxy//                                                             propionic acid                  147                                                                               CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          6-On-C.sub.3 H.sub.7                                                                 S          C(CH.sub.3).sub.2 CH(CH.sub.3)CO                                                           C.sub.2 H.sub.5                                                                   α,β,β,3,3,4                                                    ,4-                                                                            heptamethyl-1-phenyl-                                                          7-propoxy//propionic                                                           acid                            148                                                                               C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  H  5-CH.sub.3                                                                           S          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                   1-benzyl-3,3-diethyl-                                                          α,α,β,.bet                                                    a.,6-pentamethyl-                                                              propionic acid                  149                                                                               n- H  H  H  4-OH  S          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                   5-hydroxy-3-propyl-                C.sub.3 H.sub.7                             α,α,β,.bet                                                    a.-tetramethyl-                                                                1-(2-thienyl)//                                                                propionic acid                  150                                                                               H  H  H  H  H     S CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                   1-methyl//butyric                                                              acid                            151                                                                               CH.sub.3                                                                          H  H  H  H     S C.sub.2 H.sub.5                                                                         CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                           C.sub.2 H.sub.5                                                                   γ,3-dimethyl-1-ethyl/                                                    /                                                                              butyric acid                    152                                                                               CH.sub.3                                                                          CH.sub.3                                                                          H  H  H     S n-C.sub.3 H.sub.7                                                                       C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                              CH.sub.2 CO C.sub.2 H.sub.5                                                                   γ,γ-diethyl-3,3                                                    -                                                                              dimethyl-1-propyl//                                                            butyric acid                    153                                                                               CH.sub.3                                                                          CH.sub.3                                                                          n- H  H     S CH.sub.2 =CH                                                                            o(n-C.sub.3 H.sub.7).sub.2                                                                 C.sub.2 H.sub.5                                                                   3,3-dimethyl-β,γ                                                    ,γ,4-                              C.sub.3 H.sub.7        CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                              tetrapropyl-1-vinyl//                                                          butyric acid                    154                                                                               H  H  H  H  H     S CH.sub.2 =CHCH.sub.2                                                                    [C(CH.sub.3).sub.2 ].sub.2 CH.sub.2                                                        C.sub.2 H.sub.5                                                                   1-allyl-β,β,.gamm                                                    a.,γ-                                                                    tetramethyl//butyric                                                           acid                            155                                                                               H  H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-Cl  S CH.sub.2 =CH--                                                                          [C(C.sub.2 H.sub.5).sub.2 ].sub.2                                              CH(C.sub.2 H.sub.5)CO                                                                      C.sub.2 H.sub.5                                                                   7-chloro-α,β,.be                                                    ta.,γ,γ,4,-                                                        4-heptaethyl-1-vinyl//                                                         butyric acid                    156                                                                               H  H  CH.sub.3                                                                          H  4-CH.sub.3                                                                           S HC.tbd.CH                                                                               [CH(CH.sub.3).sub.2 ].sub.3 CO                                                             C.sub.2 H.sub.                                                                    1-ethynyl-α,α,.                                                    beta.,β,γ,.gamma                                                    .,-                                                                            4,5-octamethyl//                                                               butyric acid                                   O                                                                              ∥                                                      157                                                                               C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H  5-OCCH.sub.3                                                                         S CH.sub.3 C.tbd.CH                                                                       CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5                                          ].sub.2 CO  C.sub.2 H.sub.5                                                                   6-acetoxy-α,α,.                                                    beta.,β,γ,3,-                                                       3,4-octaethyl-1-                                                               (1-propynyl)//butyric                                                          acid                            158                                                                               H  H  CH.sub.3                                                                          CH.sub.3                                                                          7-OCH.sub.3                                                                          S          CH.sub.2 [C(CH.sub.3).sub.3 ].sub.2                                                        C.sub.2 H.sub.5                                                                   1-cyclobutyl-α,.alpha                                                    .,β,β,-                                                              4,4-hexamethyl-8-                                                              methoxy//butyric acid           159                                                                               H  H  H  H  4-Br  S          CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                                     C.sub.2 H.sub.5                                                                   5-bromo-1-cyclopentyl-                                                         butyric acid                    160                                                                               CH.sub.3                                                                          CH.sub.3                                                                          H  H  4-n-C.sub.3 H.sub.7                                                                  S          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                      CO         C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.alph                                                    a.-                                                                            diethyl-3,3-dimethyl-                                                          5-propyl//butyric                                                              acid                            161                                                                               H  H  H  H  7-C.sub.2 H.sub.5                                                                    S          CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                           C.sub.2 H.sub.5                                                                   8-ethyl-α-methyl-1-                                                      phenyl//butyric acid            162                                                                               CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          H  5-F   S          [CH(CH.sub.3)].sub.3 CO                                                                    C.sub.2 H.sub.5                                                                   6-fluoro-α,β,.ga                                                    mma.,3,3,4-                                                                    hexamethyl-1-phenyl//                                                          butyric acid                    163                                                                               CH.sub.3                                                                          CH.sub.3                                                                          H  H  4-CH.sub.3                                                                           S          CH(C.sub.2 H.sub.5)CH.sub.2 CH                                                             C.sub.2 H.sub.5                                                                   α,γ-diethyl-1-p                                                    henyl-                                                          (C.sub.2 H.sub.5 )CO                                                                          3,3,5-trimethyl//                                                              butyric acid                    164                                                                               C.sub.2 H.sub.5                                                                   H  H  H  6-NO.sub.2                                                                           S          [CH(CH.sub.3)].sub.3 CO                                                                    C.sub.2 H.sub.5                                                                   1-benzyl-3-ethyl-7-                                                            nitro-α,β,.gamma                                                    .-                                                                             trimethyl//butyric                                                             acid                            165                                                                               CH.sub.3                                                                          CH.sub.3                                                                          H  H  4-n-C.sub.3 H.sub.7                                                                  S          CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                       C.sub.2 H.sub.5                                                                   1-benzyl-α,β-die                                                    thyl-                                                                          3,3-dimethyl-5-                                                                propyl//butyric acid            166                                                                               H  H  H  H  7-OH  S          C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).sub                                     .2 CO       C.sub.2 H.sub.5                                                                   1-benzyl-8-hydroxy-                                                            α,α,γ,.ga                                                    mma.-tetramethyl//                                                             butyric acid                    167                                                                               CH.sub.3                                                                          H  CH.sub.3                                                                          H  4-OC.sub.2 H.sub.5                                                                   S          [C(CH.sub.3).sub.2 ].sub.3 CO                                                              C.sub.2 H.sub.5                                                                   5-ethoxy-α,α,.b                                                    eta.,β,γ,γ                                                    -                                                                              3,4-octomethyl-1-1-                                                            (2-thienyl)//                                                                  butyric acid                    168                                                                               C.sub.2 H.sub.5                                                                   H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-Cl  S          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                      CO         C.sub.2 H.sub.5                                                                   7-chloro-α,α,3,                                                    4,4-                                                                           pentaethyl-1-                                                                  (2-thienyl)//                                                                  butyric acid                    __________________________________________________________________________

EXAMPLE 169 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXALDEHYDE (XI; R¹ = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, AND Y = CO)

A mixture of the starting material, tryptophol (32.2 g, 0.2 mole), acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acid in 500 ml of benzene is refluxed for 11/2 hr. in the presence of a Dean-Stark water trap. The benzene solution is washed with 5% sodium bicarbonate, water, dried and evaporated to afford an oil. The oil is subjected to chromatography on a silica gel column using 10% ethyl acetate in benzene as eluent. The acetate, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol acetate is obtained as an oil, nmr(CDCl₃) δ 1.52(S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at room temperature. To this solution is added dropwise 20 ml of 10N NaOH. Hydrolysis is immediate. Most of the methanol is removed under reduced pressure, and water is added. The mixture is rendered neutral and extracted with chloroform. The chloroform extract is dried and evaporated to afford the primary alcohol, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol (X; R¹ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, Y = CH₂ and R¹⁷ = H), m.p. 145°-147°C., nmr(CDCl₃) δ 1.43(s,3H), 2.68(t, J = 5.5 cps,2H), 3.65 (d, J = 6 cps, 2H), 3.86 (t, J = 5.5 cps, 2H), after crystallization from benzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g, 0.084 mole) is added to a cooled, stirred solution of the above primary alcohol (6.09 g, 0.028 mole) in 63 ml of dimethyl sulfoxide-benzene (2:1) containing trifluoroacetic acid (1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reaction is stirred at room temperature under nitrogen for 5 hr. The reaction mixture is now diluted with 600 ml of ether, followed by the dropwise addition of a solution of oxalic acid (7.56 g) in 21 ml of methanol. After 30 minutes, water (600 ml) is added and the insoluble material is collected. The organic phase is washed with water (2×), 5% aqueous sodium bicarbonate (2×) and water (2×). After drying (MgSO₄) the organic phase is evaporated to yield an oil. The oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as eluate, nmr (CDCl₃) δ 1.59(s,3H), 2.84(t,J = 5.5 cps, 2H), 4.15(t, J = 5.5 cps, 2H).

Oxidation of the latter compound with silver oxide according to the method of Delepine and Bonnet, cited above, affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, nmr (CDCl₃) δ 1.79(s,3H), 2.83(t,2H), 4.17(t,2H), 9.20(1H), identical to the product obtained in Example 4.

By following the procedure of Example 169 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 168, inclusive, instead of tryptophol, and using an equivalent amount of the appropriate ketoalcohol lower alkyl ester of formula VIII, then the acid compounds of formula I in which R⁷ is hydrogen and Z is hydroxy, for example, the respective products of Examples 1 to 168, inclusive, are obtained.

More specifically exemplified, according to the procedure of Example 169 the use of indole-3-ethanethiol and acetonyl acetate affords 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid, identical to the product of Example 3. Similarly, the use of tryptophol and 5-acetoxypentan-2-one affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, identical to the product of Example 2.

EXAMPLE 170 N,N,1-TRIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]-INDOLE-1-ACETAMIDE (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O, Y = CH₂ CO AND Z = N(CH₃)₂)

To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran (300 ml), cooled to -5°C, is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5°C for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149°-151°C., γ_(max).sup. CHCl.sbsp.3 3375, 1634 cm⁻ ¹.

In the same manner but replacing dimethylamine with an equivalent amount of ammonium hydroxide (concentrated), methylamine (30% aqueous solution), n-hexylamine (20% aqueous solution), diethylamine (30% aqueous solution), or aniline (20% aqueous solution),

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 158°-160°C,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 138°-140°C,

N-(hexyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 99°C, and

N-phenyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 205°-208°C, are obtained respectively.

By following the procedure of Example 170 but using as a starting material an equivalent amount of one of the acid compounds of formula I, described in Examples 2 to 168, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine described in Example 170, then the corresponding amide compound of formula I ##EQU5## NHCH₃, N(CH₃)₂, NH(n-C₆ H₁₃) or N(C₂ H₅)₂ ] is obtained. Examples of such amides are listed as products in Tables III and IV together with the appropriate starting material and amine used for the preparation of the amide. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE III                                    __________________________________________________________________________           NO. OF THE EXAMPLE      PRODUCT: [(PREFIX LISTED BELOW-                        IN WHICH STARTING       1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                       MATERIAL IS             INDOLE-1-(SUFFIX LISTED BELOW)]                  EXAMPLE                                                                              PREPARED     AMINE        PREFIX//SUFFIX                                 __________________________________________________________________________     171   2            CH.sub.3 NH.sub.2                                                                         N,1-dimethyl//propionamide,                                                    m.p. 149-150°C.                           172   2            NH.sub.3   1-methyl//propionamide                           173   2            (CH.sub.3).sub.2 NH                                                                       N,N,1-trimethyl//propionamide                    174   2            n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//propionamide                   175   2            (C.sub.2 H.sub.5).sub.2 NH                                                                N,N,-diethyl-1-methyl//propionamide              176   4            CH.sub.3 NH.sub.2                                                                         N,1-dimethyl//carboxamide                        177   4            NH.sub.3   1-methyl//carboxamide, m.p. 188-                                               189°C.                                    178   4            (CH.sub.3).sub.2 NH                                                                       N,N,1-trimethyl//carboxamide                     179   4            n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//carboxamide                    180   4            (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-methyl//carboxamide                181   5            CH.sub.3 NH.sub.2                                                                         N,3-dimethyl-1-ethyl//carboxamide                182   8                       8-ethyl-1-ethynyl-N-phenyl//                                                   carboxamide                                      183   9            (CH.sub.3).sub.2 NH                                                                       1-cyclopropyl-N,N-dimethyl-4-iso-                                              propyl//carboxamide                              184   11           n-C.sub.16 H.sub.13 NH.sub.2                                                              N-hexyl-1-phenyl//carboxamide                    185   12           (C.sub.2 H.sub.5).sub.2 NH                                                                1-benzyl-3-methyl-N,N,3-tri-                                                   ethyl//carboxamide                               186   14           (CH.sub.3).sub.2 NH                                                                       N,N,1,4-tetramethyl//acetamide                   187   15           CH.sub.3 NH.sub.2                                                                         1-ethyl-N-methyl//acetamide                      188   15           NH.sub.3   1-ethyl//acetamide                               189   15           (CH.sub.3).sub.2 NH                                                                       N,N-dimethyl-1-ethyl//acetamide                  190   15           n-C.sub.16 H.sub.13 NH.sub.2                                                              1-ethyl-N-hexyl//acetamide                       191   15           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N,1-triethyl//acetamide                        192   16           CH.sub.3 NH.sub.2                                                                         N-methyl-1-propyl//acetamide                     193   16           NH.sub.3   1-propyl//acetamide                              194   16           (CH.sub.3).sub.2 NH                                                                       N,N-dimethyl-1-propyl//acetamide,                                              m.p. 159-162°C.                           195   16           n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-propyl//acetamide                      196   16           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-propyl//acetamide                  197   17           CH.sub.3 NH.sub.2                                                                         1-isopropyl-N-methyl//acetamide                  198   17           NH.sub.3   1-isopropyl//acetamide                           199   17           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-isopropyl//acetamide               200   19           CH.sub.3 NH.sub.2                                                                         N,3-dimethyl-1-propyl//acetamide                 201   19                      3-methyl-N-phenyl-1-propyl//                                                   acetamide                                        202   19           (CH.sub.3).sub.2 NH                                                                       1-propyl-N,N,3-trimethyl//acetamide              203   19           n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-3-methyl-1-propyl//                                                    acetamide                                        204   19           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                        205   21           CH.sub.3 NH.sub.2                                                                         N,α,1-trimethyl//acetamide                 206   21           NH.sub.3   α,1-dimethyl//acetamide                    207   21           (CH.sub.3).sub.2 NH                                                                       N,N,α,1-tetramethyl//acetamide             208   21           n-C.sub.6 H.sub.13 NH.sub.2                                                               α,1-dimethyl-N-hexyl//acetamide            209   21           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-α,1-dimethyl//                                               acetamide                                        210   22           CH.sub.3 NH.sub.2                                                                         1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                        211   23           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-phenyl//acetamide                  212   26           CH.sub.3 NH.sub.2                                                                         N,8-dimethyl-1-propyl//acetamide                 213   31           NH.sub.3   6-benzyloxy-1-methyl//acetamide                  214   32           (CH.sub.3).sub.2 NH                                                                       1-propyl-N,N,5-trimethyl//                                                     acetamide                                        215   38           n-C.sub.6 H.sub.13 NH.sub.2                                                               1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                        216   43           (CH.sub.3).sub.2 NH                                                                       1-benzyl-N,N,α,α,3-pentamethyl-                                    N                                                                              8-propionoxy//acetamide                          217   46           CH.sub.3 NH.sub.2                                                                         5-iodo-1-isopropyl-N-methyl//                                                  propionamide                                     218   49           NH.sub.3   1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                     219   54           (CH.sub.3).sub.2 NH                                                                       4,4-diethyl-N,N,α,α,β,3-hex                                   a-                                                                             methyl-1-methallyl//propionamide                 220   57           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-5-methoxy-α-methyl-                                          1-phenyl-3-propyl//propionamide                  221   62           CH.sub.3 NH.sub.2                                                                         N-methyl-α-propyl-1-(1-propynyl)-                                        3,3,5-triethyl//propionamide                     222   63                      1-cyclopropyl-α,β-diethyl-6-                                        ethoxy-N-phenyl//propionamide                    223   67           (CH.sub.3).sub.2 NH                                                                       N,N,1-trimethyl//butyramide                      224   67           CH.sub.3 NH.sub.2                                                                         N,1-dimethyl//butyramide                         225   67           NH.sub.3   1-methyl//butyramide                             226   67           n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//butyramide                     227   70           CH.sub.3 NH.sub.2                                                                         β,γ,γ ,4-tetrapropyl-N,3,3-                                   trimethyl-1-vinyl//butyramide                    228   71           (C.sub.2 H.sub.5).sub.2 NH                                                                1-allyl-N,N-diethyl-β,β,γ,.g                                   amma.-                                                                         tetramethyl//butyramide                          229   73           (CH.sub.3).sub.2 NH                                                                       N,N,α,α,β,β,γ,.g                                   amma.,4,5-decamethyl-                                                          1-ethynyl//butyramide                            230   76           NH.sub.3   5-bromo-1-cyclopentyl-α,α,β                                   -                                                                              trimethyl//butyramide                            231   78           CH.sub.3 NH.sub.2                                                                         8-ethyl-N,α-dimethyl-1-phenyl//                                          butyramide                                       232   80           (C.sub.2 H.sub.5).sub.2 NH                                                                1-phenyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                      233   82           n-C.sub.6 H.sub.13 NH.sub.2                                                               1-benzyl-α,β-diethyl-3,3-                                           dimethyl-N-hexyl-5-propyl//                                                    butyramide                                       __________________________________________________________________________

Still following the procedure of Example 170 but using the appropriate acid compound of formula I and the appropriate amine, the following additional amides are obtained.

N-Isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 151°-153°C, from 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid of Example 1 and isopropylamine.

N-Ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 152°-153°C, from 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid of Example 1 and ethylamine.

                                      TABLE IV                                     __________________________________________________________________________           NO. OF THE EXAMPLE      PRODUCT: [(PREFIX LISTED BELOW-                        IN WHICH STARTING       1,3,4,9-TETRAHYDROTHIOPYRANO-                          MATERIAL IS             [3,4-b]INDOLE-1-(SUFFIX LISTED                   EXAMPLE                                                                              PREPARED     AMINE      BELOW)] PREFIX//SUFFIX                           __________________________________________________________________________     234   3            CH.sub.3 NH.sub.2                                                                         N,1-dimethyl//acetamide                          235   3            NH.sub.3   1-methyl//acetamide                              236   3            n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//acetamide                      237   3            (CH.sub.3).sub.2 NH                                                                       N,N,1-trimethyl//acetamide, m.p.                                               182-184°C.                                238   3            (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-methyl//acetamide                  239   129          CH.sub.3 NH.sub.2                                                                         N,1-dimethyl//propionamide                       240   129          NH.sub.3   1-methyl//propionamide                           241   129          (CH.sub.3).sub.2 NH                                                                       N,N,1-trimethyl//propionamide                    242   129          n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//propionamide                   243   129          (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-methyl//propion-                                                 amide                                            244   87           CH.sub.3 NH.sub.2                                                                         N,1-dimethyl//carboxamide                        245   87           NH.sub.3   2 -246 87 (CH.sub.3).sub.2 NH N,N,1-trimethy                                   l//carboxamide                                   247   87           n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//carboxamide                    248   87           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-methyl//carboxamide                249   88           CH.sub.3 NH.sub.2                                                                         N,3-dimethyl-1-ethyl//carboxamide                250   91           NH.sub.3   8-ethyl-1-ethynyl//carboxamide                   251   92           (CH.sub.3).sub.2 NH                                                                       1-cyclopropyl-N,N-dimethyl-4-iso-                                              propyl//carboxamide                              252   94           n-C.sub.16 H.sub.13 NH.sub.2                                                              N-hexyl-1-phenyl//carboxamide                    253   95           (C.sub.2 H.sub.5).sub.2 NH                                                                1-benzyl-3-methyl-N,N,3-tri-                                                   ethyl//carboxamide                               254   97           (CH.sub.3).sub.2 NH                                                                       N,N,1,4-tetramethyl//acetamide                   255   98           CH.sub.3 NH.sub.2                                                                         1-ethyl-N-metyl//acetamide                       256   98           NH.sub.3   1-ethyl//acetamide                               257   98           (CH.sub.3).sub.2 NH                                                                       N,N-dimethyl-1-ethyl//acetamide                  258   98           n-C.sub.16 H.sub.13 NH.sub.2                                                              1-ethyl-N-hexyl//acetamide                       259   98           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N,-1-triethyl//acetamide                       260   99           CH.sub.3 NH.sub.2                                                                         N-methyl-1-propyl//acetamide                     261   99           NH.sub.3   1-propyl//acetamide                              262   99           (CH.sub.3).sub.2 NH                                                                       N,N-dimethyl-1-propyl//acetamide                 263   99           n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-propyl//acetamide                      264   99           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-propyl//acetamide                  265   100          CH.sub.3 NH.sub.2                                                                         1-isopropyl-N-methyl//acetamide                  266   100          NH.sub.3   1-isopropyl//acetamide                           267   100          (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-isopropyl//acetamide               268   102          CH.sub.3 NH.sub.2                                                                         N,3-dimethyl-1-propyl//acetamide                 269   102          NH.sub.3   3-methyl-1-propyl//acetamide                     270   102          (CH.sub.3).sub.2 NH                                                                       1-propyl-N,N,3-trimethyl//                                                     acetamide                                        271   102          n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-3-methyl-1-propyl//                                                    acetamide                                        272   102          (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                        273   104          CH.sub.3 NH.sub.2                                                                         N,α,1-trimethyl//acetamide                 274   104          NH.sub.3   α,1-dimethyl//acetamide                    275   104          (CH.sub.3).sub.2 NH                                                                       N,N,α,1-tetramethyl//acetamide             276   104          n-C.sub.6 H.sub.13 NH.sub.2                                                               α,1-dimethyl-N-hexyl//acetamide            277   104          (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-α,1-dimethyl//                                               acetamide                                        278   105          CH.sub.3 NH.sub.2                                                                         1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                        279   106          (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1-phenyl//acetamide                  280   109          CH.sub.3 NH.sub.2                                                                         N,8-dimethyl-1-propyl//acetamide                 281   111          NH.sub.3   6-bromo-1-propyl//acetamide                      282   117          (CH.sub.3).sub.2 NH                                                                       α,α-diethyl-N,N-dimethyl-8-fluor                                   o-                                                                             1-vinyl//acetamide                               283   121          n-C.sub.6 H.sub.13 NH.sub.2                                                               1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                        284   126          (CH.sub.3).sub.2 NH                                                                       1-benzyl-N,N,α,α,3-pentamethyl-                                    O                                                                              8-propionoxy//acetamide                          285   128          CH.sub.3 NH.sub.2                                                                         1-(2-thienyl)-N,α,α-trimethyl//                                    acetamide                                        286   132          NH.sub.3   1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                     287   137          (CH.sub.3).sub.2 NH                                                                       4,4,-diethyl-N,N,α,α,β,3-                                     hexamethyl-1-methally//                                                        propionamide                                     288   140          (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-5-methoxy-α-methyl-1-                                        phenyl-3-propyl//propionamide                    289   145          CH.sub.3 NH.sub.2                                                                         N-methyl-β-propyl-1-(1-propynyl)-                                         3,3,5-triethyl//propionamide                     290   146                     1-cyclopropyl-α,β-diethyl-6-                                        ethoxy-N-phenyl//propionamide                    291   150          (CH.sub.3).sub.2 NH                                                                       N,N,1-trimethyl//butyramide                      292   150          CH.sub.3 NH.sub. 2                                                                        N,1-dimethyl//butyramide                         293   150                     1-methyl-N-phenyl//butyramide                    294   150          n-C.sub.6 H.sub.13 NH.sub.2                                                               N-hexyl-1-methyl//butyramide                     295   153          CH.sub.3 NH.sub.2                                                                         β,γ,γ,4-tetrapropyl-N,3,3-                                    trimethyl-1-vinyl//butyramide                    296   154          (C.sub.2 H.sub.5).sub.2 NH                                                                1-allyl-N,N-diethyl-β,β,γ,.g                                   amma.-                                                                         tetramethyl//butyramide                          297   155          (CH.sub.3).sub.2 NH                                                                       7-chloro-N,N-dimethyl-α,β,β,                                   γ,γ,-                                                              4,4-heptaethyl-1-ethynyl//butyramide             298   159          NH.sub.3   5-bromo-1-cyclopentyl-α,α,β                                   -                                                                              trimethyl//butyramide                            299   161          CH.sub.3 NH.sub.2                                                                         N,α-dimethyl-8-ethyl-1-phenyl//                                          butyramide                                       300   163          (C.sub.2 H.sub.5).sub.2 NH                                                                1-phenyl-N,N,α,γ-tetraethyl-                                       3.3.5-trimethyl//butyramide                      301   165          n-C.sub.6 H.sub.13 NH.sub.2                                                               1-benzyl-α,β-diethyl-3,3-dimethyl                                   -                                                                              N-hexyl-5-propyl//butyramide                     302   168          CH.sub.2 NH.sub.2                                                                         7-chloro-N-methyl-α,α,3,4,4-                                       pentaethyl-1-(2-thienyl)//                                                     butyramide                                       __________________________________________________________________________

EXAMPLE 303 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXAMIDE (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, Y = CO AND Z = NH₂)

By following the procedure of Example 1 but using an equivalent amount of pyruvamide instead of ethyl acetoacetate, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxamide, m.p. 188°-189°C. after recrystallization from benzene-hexane, identical with the product of Example 177, is obtained.

In the same manner but using an equivalent amount of the appropriate starting material of formula II in place of tryptophol together with the appropriate α-, β-, γ- or δ-ketoamide, the products listed in Tables III and IV may be obtained. For example, by using tryptophol (II; R², R³, R⁴, R⁵, R⁶ = H and X' = OH) and the β-ketoamide, N,N-dimethyl-acetoacetamide, in the procedure of this Example, N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, identical with the product of Example 170, is obtained.

EXAMPLE 304 1,9-DIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ AND R⁷ = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, X = O, Y = CH₂ CO AND Z = OH

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (10 g., 0.04 mole), prepared as described in Example 1, in 150 ml. of tetrahydrofuran is added dropwise to a stirred suspension of sodium hydride (4.4 g. of 55% dispresion) in 200 ml. of tetrahydrofuran. This mixture is heated at 50°C. with stirring for 2 hr. Methyl iodide (14.2 g. 0.1 mole) is added dropwise and heating and stirring is continued for a further 2 hr.

After cooling, water is added until the solution is clear. The tetrahydrofuran is evaporated off under reduced pressure, the residue is partition between water and benzene. The aqueous phase is washed once with benzene, made acidic with HCl, and extracted with benzene (3×). The organic phase is washed with water, dried over sodium sulfate and treated with charcoal. The organic layer is evaporated. The residue is crystallized from benzene and then ether-petroleum ether to afford the title compound, m.p. 105°-108°C., nmr (CDCl₃) δ 1.73 (S,3H), 2.83 (t, J = 5.5, 2H), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H), 9.47 (1H).

In the same manner but replacing methyl iodide with an equivalent amount of ethyl iodide, or propyl iodide 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 134°-136°C., and 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid, m.p. 120°-122°C., are obtained, respectively.

By following the procedure of Example 304 but using the starting material an equivalent amount of the acid compounds of formula I, compounds of formula I in which R⁷ is hydrogen and Z is hydroxy, described in Examples 1 to 168, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, and using an equivalent amount of an appropriate lower alkyl or lower alkenyl halide, then the corresponding N-alkylated acid compounds of formula I in which R⁷ is lower alkyl or lower alkenyl are obtained. Examples of these latter compounds are listed as products in Tables V and VI together with the appropriate starting material and alkyl or alkynl halide used for their preparation. In each case the starting material is noted by the Example in which it is prepared.

                                      TABLE V                                      __________________________________________________________________________           NO. OF THE EXAMPLE       PRODUCT: [(PREFIX LISTED BELOW-                       IN WHICH STARTING        1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                      MATERIAL IS  ALKYL OR ALKENYL                                                                           INDOLE-1-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                              PREPARED      HALIDE                                                                                    PREFIX//SUFFIX                                  __________________________________________________________________________     305   1            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-methyl//acetic acid,                                                 m.p. 103-105°C.                          306   1            CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//acetic acid                   307   1            CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           1-methyl-9-methallyl//acetic acid               308   2            n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid               309   2            CH.sub.3 I  1,9-dimethyl//propionic acid, m.p.                                             129-130°C.                               310   2            CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//propionic acid                311   2            CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//propionic acid                312   4            CH.sub.3 I  1,9-dimethyl//carboxylic acid                   313   4            CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//carboxylic acid               314   7            CH.sub.3 I  6-hydroxy-1-(1-propenyl)-3,3,9-                                                trimethyl//carboxylic acid                      315   9            CH.sub.3 CH=CHBr                                                                           1-cyclopropyl-4-isopropyl-9-                                                   (1-propenyl)//carboxylic acid                   316   11           i-C.sub.3 H.sub.7 I                                                                        9-isopropyl-1-phenyl//carboxylic                                               acid                                            317   15           CH.sub.3 I  1-ethyl-9-methyl//acetic acid                   318   15           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                        319   15           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-ethyl//acetic acid                    320   15           CH.sub.2 =CHBr                                                                             1-ethyl-9-vinyl//acetic acid                    321   16           CH.sub.3 I  9-methyl-1-propyl//acetic acid                  322   16           n-C.sub.2 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                       323   16           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-propyl//acetic acid                   324   16           CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           9-methallyl-1-propyl//acetic acid               325   17           CH.sub.3 I  9-methyl-1-isopropyl//acetic acid               326   17           CH.sub.2 =CHBr                                                                             1-isopropyl-9-vinyl//acetic acid                327   19           n-C.sub.3 H.sub.7 Cl                                                                       1-9-dipropyl-3-methyl//acetic acid              328   19           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-3-methyl-1-propyl//acetic                                              acid                                            329   21           CH.sub.3 I  α,1,9-trimethyl//acetic acid              330   21           CH.sub.2 =CHBr                                                                             α,1-dimethyl-1-vinyl//acetic acid         331   22           n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                       propyl//acetic acid                             332   27           CH.sub.2 =CHCH.sub.2 I                                                                     9-allyl-1-(2-thienyl)//acetic acid              333   29           CH.sub.3 Cl 1,9-dimethyl-6-methoxy//acetic acid             334   34           CH.sub.2 =CHBr                                                                             6-nitro-1-propyl-9-vinyl//                                                     acetic acid                                     335   40           C.sub.2 H.sub.5 Cl                                                                         α,3-dimethyl-9-ethyl-1-phenyl-                                           4,4,5-tripropyl//acetic acid                    336   42           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-benzyl-α,α-diisopropy                                    l-                                                                             3,3,4,4,5-pentaethyl//acetic acid               337   48           C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(2-propynyl)-β,β,9-                                      triethyl//propionic acid                        338   49           CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-nitro-                                             α-propyl//propionic acid                  339   54           CH.sub.2 =C(CH.sub.3)CH.sub.2 Cl                                                           4,4-diethyl-1,9-dimethallyl-α,α                                    ,β,-                                                                      3-tetramethyl//propionic acid                   340   59           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-8-chloro-β,3,3,4,4-                                               pentamethyl-1-(2-thienyl)//                                                    propionic acid                                  341   60           CH.sub.2 =CHCl                                                                             1-methyl-6-nitro-α,α,β,.be                                    ta.,3-penta-                                                                   ethyl-9-vinyl//propionic acid                   342   63           C.sub.2 H.sub.5 Cl                                                                         1-cyclopropyl-6-ethoxy-α,β,9-                                       triethyl//propionic acid                        343   67           CH.sub.3 I  1,9-dimethyl//butyric acid                      344   67           CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//butyric acid                  345   68           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//butyric                                        acid                                            346   70           CH.sub.2 =CHBr                                                                             3,3-dimethyl-1,9-divinyl-β,γ,.ga                                    mma.,-                                                                         4-tetrapropyl//butyric acid                     347   72           CH.sub.2 =CHBr                                                                             7-chloro-1,9-divinyl-α,β,β,                                    γ,γ,-                                                              4-heptaethyl//butyric acid                      348   78           C.sub.2 H.sub.5 I                                                                          8,9-diethyl-α-methyl-1-phenyl//                                          butyric acid                                    349   82           CH.sub.3 I  1-benzyl-α,β-diethyl-5-propyl-                                      3,3,9-trimethyl//butyric acid                   350   85           C.sub.2 H.sub.5 Br                                                                         7-chloro-α,α,3,4,4,9-hexaethyl-                                    1-(2-thienyl)//butyric acid                     __________________________________________________________________________

                                      TABLE VI                                     __________________________________________________________________________           NO. OF THE EXAMPLE       PRODUCT: [(PREFIX LISTED BELOW-1,3,-                  IN WHICH STARTING        4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                      MATERIAL IS  ALKYL OR ALKENYL                                                                           INDOLE-1-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                              PREPARED      HALIDE     PREFIX//SUFFIX                                  __________________________________________________________________________     351   3            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-methyl//acetic acid                   352   3            CH.sub.3 I  1,9-dimethyl//acetic acid                       353   3            CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           1-methyl-9-methallyl//acetic                                                   acetic acid                                     354   129          n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic                                                   acid                                            355   129          CH.sub.3 I  1,9-dimethyl//propionic acid                    356   129          CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//propionic acid                357   129          CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//propionic acid                358   87           CH.sub.3 I  1,9-dimethyl//carboxylic acid                   359   87           CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//carboxylic                                                   acid                                            360   90           CH.sub.3 I  6-hydroxy-1-(1-propenyl)-3,3,9-                                                trimethyl//carboxylic acid                      361   92           CH.sub.3 CH=CHBr                                                                           1-cyclopropyl-4-isopropyl-9-                                                   (1-propenyl)//carboxylic acid                   362   94           2-C.sub.3 H.sub.7 I                                                                        9-isopropyl-1-phenyl//carboxylic                                               acid                                            363   98           CH.sub.3 I  1-ethyl-9-methyl//acetic acid                   364   98           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                        365   98           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-ethyl//acetic acid                    366   98           CH.sub.2 =CHBr                                                                             1-ethyl-9-vinyl//acetic acid                    367   99           CH.sub.3 I  9-methyl-1-propyl//acetic acid                  368   99           n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                       369   99           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-propyl//acetic acid                   370   99           CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           9-methallyl-1-propyl//acetic                                                   acid                                            371   100          CH.sub.3 I  9-methyl-1-isopropyl//acetic                                                   acid                                            372   100          CH.sub.2 =CHBr                                                                             1-isopropyl-9-vinyl//acetic                                                    acid                                            373   102          n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic                                                  acid                                            374   102          CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-3-methyl-1-propyl//                                                    acetic acid                                     375   104          CH.sub.3 I  α,1,9-trimethyl//acetic acid              376   104          CH.sub.2 =CHBr                                                                             α,1-dimethyl-1-vinyl//acetic                                             acid                                            377   105          n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                       propyl//acetic acid                             378   110          CH.sub.2 =CHCH.sub.2 I                                                                     9-allyl-1-(2-thienyl)//acetic                                                  acid                                            379   112          CH.sub.3 Cl 1,9-dimethyl-6-methoxy//                                                       acetic acid                                     380   117          CH.sub.2 =CHBr                                                                             α,α-diethyl-1,9-divinyl-8-                                         fluoro//acetic acid                             381   123          C.sub.2 H.sub.5 Cl                                                                         α,3-dimethyl-9-ethyl-1-phenyl-                                           4,4,5-tripropyl//acetic                                                        acid                                            382   125          CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-benzyl-α,α-                                              diisopropyl-3,3,4,4,5-                                                         pentaethyl//acetic acid                         383   131          C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(2-propynyl)-                                                      β,β,9-triethyl//propionic acid        384   132          CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-                                                   nitro-α-propyl//propionic acid            385   137          CH.sub.2 =C(CH.sub.3)CH.sub.2 Cl                                                           4,4-diethyl-1,9-dimethallyl-                                                   α,α,β,3-tetramethyl//propi                                    onic                                                                           acid                                            386   142          CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-8-chloro-β,3,3,4,4-                                               pentamethyl-1-(2-thienyl)//                                                    propionic acid                                  387   143          CH.sub.2 =CHCl                                                                             1-methyl-6-nitro-α,α,β,.be                                    ta.,3-penta-                                                                   ethyl-9-vinyl//propionic acid                   388   146          C.sub.2 H.sub.5 Cl                                                                         1-cyclopropyl-6-ethoxy-α,β,9-                                       triethyl//propionic acid                        389   150          CH.sub.3 I  1,9-dimethyl//butyric acid                      390   150          CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//butyric acid                  391   151          C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//                                               butyric acid                                    392   153          CH.sub.2 =CHBr                                                                             3,3-dimethyl-1,9-divinyl-β,γ,.ga                                    mma.,-                                                                         4-tetrapropyl//butyric acid                     393   155          CH.sub.2 =CHBr                                                                             7-chloro-1,9-divinyl-α,β,β,                                    γ,γ,-                                                              4,4-heptaethyl//butyric acid                    394   161          C.sub.2 H.sub.5 I                                                                          8,9-diethyl-α-methyl-1-phenyl//                                          butyric acid                                    395   165          CH.sub.3 I  1-benzyl-α,β-diethyl-5-propyl-                                      3,3,9-trimethyl//butyric acid                   396   168          C.sub.2 H.sub.5 Br                                                                         7-chloro-α,α,3,4,4,9-hexaethyl-                                    1-(2-thienyl)//butyric acid                     __________________________________________________________________________

EXAMPLE 397

By following the procedure of Example 304 but using as the starting material an equivalent amount of the ester compounds of formula I in which R⁷ is hydrogen and Z is lower alkoxy, obtained prior to hydrolysis in Example 1 and 3 to 168, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, and using an equivalent amount of an appropriate lower alkyl or lower alkenyl halide, then the corresponding N-alkylated ester compounds of formula I in which R⁷ is lower alkyl or lower alkenyl, are obtained.

For example, when following the procedure of Example 304, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid by an equivalent amount of its corresponding ethyl ester, described in Example 1, and then use the same alkyl halide, methyl iodide, affords 1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester.

Similarly, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, described in Example 3, affords 1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester.

By following the procedure of Example 170 but using as the starting material an equivalent amount of one of the N-alkylated acid compounds of formula I, described in Examples 304 to 396, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine, described in Example 170, then the corresponding amide compound of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is amino, lower alkyl amino, di(lower)alkylamino or phenylamino, is obtained. Examples of such amides are listed as products in Tables VII and VIII together with the appropriate starting material, noted by the example in which it is prepared, and the amine used for the preparation of the amide.

                                      TABLE VII                                    __________________________________________________________________________           NO. OF THE EXAMPLE PRODUCT: [(PREFIX LISTED BELOW-                             IN WHICH STARTING  1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                            MATERIAL IS        INDOLE-1-(SUFFIX LISTED BELOW)]                       EXAMPLE                                                                              PREPARED     AMINE PREFIX/SUFFIX                                         __________________________________________________________________________     398   304          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide,                                                ν.sub.max.sup.CHCl .sbsp.3 1620, 1070                                       cm.sup..sup.-1, nmr                                                            (CDCl.sub.3) δ 1.71, 2.76, 2.89,                                         3.00, 3.71                                            399   304          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide, m.p.                                               136-138°C.                                     400   304          NH.sub.3                                                                             1,9-dimethyl//acetamide, m.p.                                                  105-106°C.                                     401   304          n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                       402   304          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//                                                     acetamide,                                                                     ν.sub.max.sup.CHCl .sbsp.2 1630                                             cm.sup.-.sup.1,                                                                nmr (CDCl.sub.3) γ 1.10, 1.74, 2.80,                                     3.97.                                                 403   305          CH.sub.3 NH.sub.2                                                                    9-allyl-N,1-dimethyl//acetamide                       404   305          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                      acetamide                                             405   309          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide,                                                 m.p. 148-150°C.                                406   309          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//                                                     propionamide                                          407   311          NH.sub.3                                                                             9-allyl-1-methyl//propionamide                        408   311          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                      propionamide                                          409   313          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-vinyl//                                                         carboxamide                                           410   314          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1-                                                       (1-propenyl)-3,3,9-trimethyl//                                                 carboxamide                                           411   316          n-C.sub.6 H.sub.3 NH.sub.2                                                           N-hexyl-9-isopropyl-1-phenyl//                                                 carboxamide                                           412   317          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//acetamide                       413   319          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N,1-triethyl//                                                       acetamide                                             414   320          (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl-9-vinyl//                                                 acetamide                                             415   321          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//                                                        acetamide                                             416   323          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                             417   331          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                                  418   332          n-C.sub.6 H.sub.13 NH.sub.2                                                          9-allyl-N-hexyl-1-(2-thienyl)//                                                acetamide                                             419   333          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                                acetamide, m.p. 118-120°C.                     420   335          CH.sub.3 NH.sub.2                                                                    9-ethyl-1-phenyl-4,4,5-                                                        tripropyl-N,α,3-trimethyl//                                              acetamide                                             421   341          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N,α,α,β,β,3-heptaethyl-1-                              N                                                                              methyl-6-nitro-9-vinyl//                                                       propionamide                                          422   342          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-methoxy-N,N,-                                                  α,β,9-pentaethyl-9-vinyl//                                          propionamide                                          423   343          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                           424   344          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                      butyramide                                            425   345          NH.sub.3                                                                             1,9-diethyl-γ,3-dimethyl//                                               butyramide                                            426   349          CH.sub.3 NH.sub.2                                                                    1-benzyl-α,β-diethyl-5-propyl-                                      N,3,3,9-tetramethyl//                                                          butyramide                                            __________________________________________________________________________

                                      TABLE VIII                                   __________________________________________________________________________           NO. OF THE EXAMPLE PRODUCT: [(PREFIX LISTED BELOW-1,3,                         IN WHICH STARTING  4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                            MATERIAL IS        INDOLE-1-(SUFFIX LISTED BELOW)]                       EXAMPLE                                                                              PREPARED     AMINE PREFIX//SUFFIX                                        __________________________________________________________________________     427   352          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide,                                                ν.sub.max.sup.CHCl .sbsp.3 1625                                             cm.sup.-.sup.1, nmr (CDCl.sub.3)                                               δ 2.23, 3.65.                                   428   352          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide, m.p.                                               127-128°C.                                     429   352          NH.sub.3                                                                             1,9-dimethyl//acetamide                               430   352          n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                       431   352          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//                                                     acetamide                                             432   351          CH.sub.3 NH.sub.2                                                                    9-allyl-N,1-dimethyl//acetamide                       433   351          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                      acetamide                                             434   355          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide                         435   355          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//                                                     propionamide                                          436   357          NH.sub.3                                                                             9-allyl-1-methyl//propionamide                        437   357          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                      propionamide                                          438   359          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-vinyl//                                                         carboxamide                                           439   360          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1-                                                       (1-propenyl)-3,3,9-trimethyl//                                                 carboxamide                                           440   362          n-C.sub.6 H.sub.3 NH.sub.2                                                           N-hexyl-9-isopropyl-1-phenyl//                                                 carboxamide                                           441   363          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//                                                         acetamide                                             442   365          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N,1-triethyl//                                                       acetamide                                             443   366          (CH.sub.3).sub. 2 NH                                                                 N,N-dimethyl-1-ethyl-9-vinyl//                                                 acetamide                                             444   367          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//acetamide                      445   369          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                             446   377          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                                  447   378          n-C.sub.6 H.sub.13 NH.sub.2                                                          9-allyl-N-hexyl-1-(2-thienyl)//                                                acetamide                                             448   379          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                                acetamide                                             449   381          CH.sub.3 NH.sub.2                                                                    9-ethyl-1-phenyl-4,4,5-                                                        tripropyl-N,α,3-trimethyl//                                              acetamide                                             450   387          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N,α,α,β,β,3-heptaethyl-1-                              N                                                                              methyl-6-nitro-9-vinyl//                                                       propionamide                                          451   388          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-ethoxy-N,N,-                                                   α,β,9-pentaethyl//propionamide             452   389          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                           453   390          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                      butyramide                                            454   391          NH.sub.3                                                                             1,9-diethyl-γ,3-dimethyl//                                               butyramide                                            455   395          CH.sub.3 NH.sub.2                                                                    1-benzyl-α,β-diethyl-5-propyl-                                      N,3,3,9-tetramethyl//butyramide                       __________________________________________________________________________

Still following the procedure of Example 170 but using the appropriate acid compound of formula I and the appropriate amine, the following additional amides are obtained:

N,N,1-Trimethyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 84°-87°C., from 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid of Example 304 and dimethylamine.

9-Ethyl-N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 108°-109°C, from 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid of Example 304 and methylamine.

9-Ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 130°-133°C, from 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid of Example 304 and ammonia.

N,N,1,9-Tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionamide, ν_(max) ^(CHCl).sbsp.3 1622 cm⁻ ¹, nmr (CDCl₃) δ 1.61, 2.80, 3.74, from 1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, m.p. 129°-130°C, of Example 309 and dimethylamine.

6-Benzyloxy-N,N,1,9-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, nmr (CDCl₃) δ 1.73, 2.75, 3.75, 3.97, from 6-benzyloxy-1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 167°-168°C, and dimethylamine; the latter acid being obtained from 6-benxyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid of Example 31 according to the procedure of Example 304.

5-Chloro-N,N,1,9-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, ν_(max) ^(CHCl).sbsp.3 1623 cm⁻ ¹, nmr (CDCl₃) δ 1.72, 2.93, 3.08, 3.15, 3.95, from 5-chloro-1,9-dimethyl- 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid m.p. 105°-110°C and dimethylamine, the latter acid being obtained from 5-chloro-1-methyl-1,3,4,9-tetrapyrano[3,4-b]indole-1-acetic acid of Example 463 according to the procedure of Example 304.

6-Benzyloxy-9-ethyl-N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, ν_(max) ^(CHCl).sbsp.3 1625, 115, 1080 cm.sup.⁻¹, from 6-benzyloxy-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, nmr (CDCl₃) δ1.73 (s, 3H), 5.12 (s, 2H), and dimethylamine; the latter acid being obtained from 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid of Example 31 by reaction with ethyl iodide according to the procedure of Example 304.

N,N,1,5,9-Pentamethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, ν_(max) ^(CHCl).sbsp.3 1620 cm.sup.⁻¹, nmr (CDCl₃) δ 1.75, 2.66, 2.96, 3.08, 3.78, from 1,5,9-trimethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid, m.p. 132°-134°C, and dimethylamine; the latter acid being obtained from 1,5-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid of Example 467 according to the procedure of Example 304.

EXAMPLE 456 6-HYDROXY-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b] -INDOLE1-ACETIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵ AND R⁷ = H, R⁶ = 6-OH, X = O, Y = CH₂ CO and Z = OH)

A mixture of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (5.3 g., 0.015 mole), prepared as described in Example 31, in 250 ml. of anhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere until no more hydrogen is being taken up by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate concentrated. The residue is recrystallized from ethanol-benzene to afford the title compound,m.p. 170°-171°C.

The corresponding benzylamine salt is prepared by the mixing of equimolar ethereal solutions of benzylamine and the above product. The resulting solid is recrystallized from acetonitrile to afford 6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid benzylamine salt, m.p. 191°-193°C. The corresponding acetate is prepared by allowing a mixture of the title compound and a five molar excess of acetic anhydride in pyridine solution to stand for 24 hr. Dilution of the mixture with water extraction with ether and recrystallization of the extract residue from benzene-petroleum ether, affords 6-acetoxy-1-methyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid, identical with the product of Example 30.

Table IX provides further examples of the compounds of this invention. The remarks relating to procedure, starting material and product applied to Table I are applicable also to Table IX. Note also that starting materials of both formulae II and IIa are utilized.

                                      TABLE IX                                     __________________________________________________________________________                                   KETOESTER OF PRODUCT: [(PREFIX                                                 FORMULA VI   LISTED BELOW)-1,3,4,9-                                            O            TETRAHYDROPYRANO-                         STARTING MATERIAL OF    ∥   [3,4-b]INDOLE-1-                    EXAMPLE                                                                              FORMULA II              (R.sup.1 --C--Y--OR.sup.16)                                                                 (SUFFIX LISTED BELOW)]              R.sup.2   R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                           R.sup.6                                                                               X R.sup. 1                                                                            Y   R.sup.16                                                                           PREFIX//SUFFIX                      __________________________________________________________________________     457   H   H   CH.sub.3                                                                           H  H      O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    4-methyl-1-propyl//                                                            acetic acid, m.p.                                                              191-195°C.                   458   H   H   H   H  5-CH.sub.3                                                                            O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    6-methyl-1-propyl//                                                            acetic acid, m.p.                                                              126-129°C.                   459   H   H   H   H  4-i-C.sub.3 H.sub.7                                                                   O n-C.sub.3 H.sub.7                                                                   CH.sub. 2 CO                                                                       C.sub.2 H.sub.5                                                                    5-isopropyl-1-propyl//                                                         acetic acid, m.p.                                                              164.5-165°C.                 460   H   H   H   H  4-Cl   O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-chloro-1-propyl//                                                            acetic acid, m.p.                                                              166-169°C.                   461   H   H   H   H  6-OCH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7-methoxy-1- propyl//                                                          acetic acid, m.p.                                                              164-166°C.                   462   H   H   CH.sub.3                                                                           H  H      O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-4-methyl//                                                             acetic acid, m.p.                                                              153-156°C.,                                                             (Isomer A), m.p.                                                               132-133°C (Isomer B)         463   H   H   H   H  4-Cl   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-chloro-1-methyl//                                                            acetic acid, m.p.                                                              183-184°C.                   464   H   H   H   H  4-C.sub.2 H.sub.5                                                                     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-ethyl-1-propyl//                                                             acetic acid, m.p.                                                              130-131°C.                   465   H   CH.sub.3                                                                           H   H  H      O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-3-methyl//                                                             acetic acid, m.p.                                                              147-148°C.,                                                             (Isomer A), m.p.                                                               145-146°C.,                                                             (Isomer B)                          466   H   H   H   H  4-CH.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-5-methyl//                                                             acetic acid, m.p.                                                              170-172°C.                   467   H   H   H   N  4-CH.sub.3                                                                            O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1.5-dimethyl//acetic                                                           acid, m.p. 150-151°C.        468   H   H   H   H  4-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-chloro-1-ethyl//                                                             acetic acid, m.p.                                                              154-157°C.                   469   H   H   CH.sub.3                                                                           H  H      O t-C.sub.4 H.sub.9                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-t-butyl-4-methyl//                                                           acetic acid, m.p.                                                              179-181°C.                   470   H   H   H   H  4-OCH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-methoxy-1-propyl//                                                           acetic acid, m.p.                                                              148-151°C.                   471   H   H   H   H  7-CN.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-8-methyl//                                                             acetic acid, m.p.                                                              160-161°C.                   472   H   H   CH.sub.3                                                                           H  7-CH.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    4,8-dimethyl-1-ethyl//                                                         acetic acid, m.p.                                                              129-131°C.                   473   H   H   CH.sub.3                                                                           H  7-CH.sub.3                                                                            O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1,4,8-trimethyl//                                                              acetic acid, m.p.                                                              157-159°C.                   474   H   H   H   H  7-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    8-chloro-1-ethyl//                                                             acetic acid, m.p.                                                              168-171°C.                   475   H   H   H   H  6-Cl   0 c.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7-chloro-1-ethyl//                                                             acetic acid, m.p.                                                              182-183°C.                   476   H   H   H   H  6-Cl   O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7-chloro-1-propyl//                                                            acetic acid, m.p.                                                              182-183°C.                   477   H   H   H   H  7-C.sub.2 H.sub.5                                                                     O C.sub. 2 H.sub.5                                                                    CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1,8-diethyl//acetic                                                            acid, m.p. 145-148°C.        478   H   H   H   H  7-OCH.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-8-methoxy//                                                            acetic acid, m.p.                                                              132°C.                       479   H   H   H   H  4-CH.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub. 2 H.sub.5                                                                   5,8-dimethyl-1-ethyl//                                   7-CH.sub.3            acetic acid                         480   H   H   H   H  4-Cl   O C.sub.2 5                                                                           CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5,8-dichloro-1-ethyl//                                   7-Cl                  acetic acid                         481   H   H   H   H  6-Cl   O n-C.sub.3 H.sub.7                                                                   CH.sub.2 COo                                                                       C.sub.2 H.sub.5                                                                    7,8-dichloro-1-propyl//                                  7-Cl                  acetic acid                         482   H   H   H   H  4-Cl   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5,7-dichloro-1-methyl//                                  6-Cl                  acetic acid                         483   H   H   H   H  4-CH.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    8-chloro-1-ethyl-                                        7-Cl                  5-methyl//acetic                                                               acid                                484   H   H   H   H  4-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-chloro-1-ethyl-8-                                      7-CH.sub.3            methyl//acetic acid                 485   H   H   CH.sub.3                                                                           H  4-C.sub.2 H.sub.5                                                                     O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7-bromo-1,5-diethyl-                                     6-Br                  4-methyl//acetic                                                               acid                                486   H   H   H   H  6-Cl   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7-chloro-1,8-dimethyl//                                  7-CH.sub.3            acetic acid                         487   H   H   CH.sub.3                                                                           H  4-Cl   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1,4-dimethyl-5,7,8-                                      6-CCl                 trichloro//acetic                                        acid                                                      488   H   H   H   H  4-CCH.sub.  3                                                                         O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-propyl-5,6,7,8-                                        5-OCH.sub.3           tetramethoxy//                                           6-OCH.sub.3           acetic acid                                              7-OCH.sub.3                                               489   H   H   H   H  4-OCH.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub. 2 H.sub.5                                                                   8-chloro-1-ethyl-5-                                      7-Cl                  methoxy//acetic                                                                acid                                490   H   H   CH.sub.3                                                                           H  4-OCH.sub.3                                                                           O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7,8-dichloro-1-                                                                methyl-5-methoxy//                                       6-Cl                  acetic acid                                              7-Cl                                                      491   H   H   H   H  4-OCH.sub.3                                                                           O C.sub. 2 H.sub.5                                                                    CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-5,8-di-                                                                methoxy//acetic acid                                     7-OCH.sub.3           m.p. 167-169°C.              492   CH.sub.3                                                                           H   H   H  4-F    O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    8-chloro-5-fluoro-3-                                                           methyl-1-propyl//                                        7-Cl                  acetic acid                         493   H   H   H   H  4-F    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    7,8-dichloro-5-                                          6-Cl                  fluoro-1-ethyl//                                         7-Cl                  acetic acid                         494   C.sub.2 H.sub.5                                                                    H   CH.sub.3                                                                           H  4-CF.sub.3                                                                            O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    3-ethyl-5-trifluoro-                                     7-CH.sub.3            methyl-1,4,8-                                                                  trimethyl//acetic                                                              acid                                495   H   H   H   H  6-CF.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-7-trifluoro-                                                           methyl//acetic acid                 496   H   H   CH.sub.3                                                                           H  7-CF.sub.3                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-4-methyl-8-                                                            trifluoromethyl//                                                              acetic acid                         497   H   H   C.sub.2 H.sub.5                                                                    H  5-CH.sub.3                                                                            O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1,6-dimethyl-4-ethyl-                                    7-NO.sub.2            8-nitro//acetic acid                498   CH.sub.3                                                                           H   H   H  4-NO.sub.2                                                                            O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C 2H.sub.5                                                                         8-chloro-3-methyl-5-                                     7-Cl                  nitro-1-propyl//                                                               acetic acid                         499   H   H   H   H  5-SH   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub. 2 H.sub.5                                                                   6-mercapto-1-methyl//                                                          acetic acid                         500   H   H   CH.sub. 3                                                                          H  7-SCH.sub.3                                                                           O CH.sub.3                                                                            CH.sub.2 -                                                                         C.sub.2 H.sub.5                                                                    1,4-dimethyl-8-methyl-                                                 CH.sub.2 CO                                                                            thio//propionic acid                501   H   H   H   H  6-SC.sub.2 H.sub.5                                                                    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-ethyl-7-ethylthio//                                                          acetic acid                         502   H   H   H   H  4-NH.sub.  2                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-amino-1-ethyl//                                                              acetic acid                         503   H   H   H   H  6-NH.sub.2                                                                            O C.sub.2 H.sub.5                                                                     CH.sub.2 Co                                                                        C.sub.2 H.sub.5                                                                    7-amino-1-ethyl//                                                              acetic acid                         504   H   H   H   H  4-SO.sub.2 NH.sub.2                                                                   O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-propyl-5-sulfamoyl//                                                         acetic acid                         505   H   H   H   H  6-SO.sub.2 NH.sub.2                                                                   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-methyl-7-sulfamoyl//                                                         acetic acid                         __________________________________________________________________________ 

We claim:
 1. A compound of the formula ##SPC12##wherein R¹ is lower alkyl having from 1 to 6 carbon atoms; R⁶ is hydrogen or methoxy; R⁷ is hydrogen or lower alkyl having from 1 to 6 carbon atoms; X is oxy or thio, Y is CO, CH₂ CO or CH₂ CH₂ CO and Z is amino, methylamino, dimethylamino, diethylamino or phenylamino.
 2. A compound of the formula ##SPC13##wherein R¹ is lower alkyl having from 1 to 6 carbon atoms; R⁶ is hydrogen, chlorine, methyl or benzyloxy; R⁷ is hydrogen or lower alkyl having from 1 to 6 carbon atoms; X is oxy; Y is CH₂ CO or CH₂ CH₂ CO and Z is amino, methylamino, ethylamino, isopropylamino or dimethylamino.
 3. N,N-Diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 4. N,N-Dimethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 5. N-Isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 6. N-Ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 7. N,N,1-Trimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 8. N,N,1,9-Tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 9. N,1,9-Trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 10. 1,9-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 11. N,N-Diethyl-1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetamide, as claimed in claim
 1. 12. N,1,9-Trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionamide, as claimed im claim
 1. 13. 6-Methoxy-N,N,1,9-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetamide, as claimed in claim
 1. 14. N,N,1,9-Tetramethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 15. N,1,9-Trimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 16. N,N,1-Trimethyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 17. 9-Ethyl-N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 18. 9-Ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 1. 19. N,N,1,9-Tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionamide, as claimed in claim
 1. 20. 6-Benzyloxy-N-N,1-9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 2. 21. 5-Chloro-N,N-1,9-tetramethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetamide, as claimed in claim
 2. 22. 6-Benzyloxy-9-ethyl-N,N,1-trimethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetamide, as claimed in claim
 2. 23. N,N,1,5,9-Pentamethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, as claimed in claim
 2. 